Alkenoic acid derivatives

ABSTRACT

An alkenoic acid derivative of the formula ##STR1## in which X and Y are identical or different and represent sulfur, sulfoxide, sulfone, an alkylene chain, --SCH 2  --, or oxygen or a direct bond, 
     W represents --CH═CH--or --CH 2  --CH 2  --, 
     o represents a number 1 to 5, 
     A and B are identical or different and represent carboxyl, carboxymethylene, tetrazolyl or tetrazolylmethylene, or --CO 2  R 9  or --CH 2  CO 2  R 9  or --CONR 10  R 11  or nitrile 
     n represents a number 1 to 10, 
     m represents a number 0 to 7, 
     T and Z are identical or different and represent oxygen or a direct bond and 
     R 2 , R 3 , R 8  are identical or different and represent hydrogen, alkyl, alkoxy, halogen, trifluoromethyl, trifluoromethoxy, cyano or nitro and 
     R 9  is lower alkyl and R 10  and R 11  are hydrogen, lower alkyl, alkylsulfonyl or arylsulfonyl or together are an alkylene chain to form a ring 
     and pharmaceutically acceptable salts thereof. Such alkenoic acid derivatives are useful as leucotriene disease antagonists.

This is a division of application Ser. No. 07/349,371, filed May 9,1989, now U.S. Pat. No. 5,041,638.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to alkenoic acid derivatives, processes for theirpreparation and their use in medicaments.

2. Background Information

The GB 2 184 121 describes phenethyl sulphides with leukotrieneantagonistic properties. The more active compounds of the GB 2 184 121are insufficiently stable for pharmaceutical use.

SUMMARY OF THE INVENTION

New alkenoic acid derivatives of the general formula (I) ##STR2## inwhich X and Y are identical or different and represent sulfur,sulfoxide, sulfone, an alkylene chain, a direct bond, --SCH₂ -- oroxygen

W represents --CH═CH-- or --CH₂ --CH₂ --

o represents a number 1 to 5

A and B are identical or different and represent carboxyl,carboxymethylene, tetrazolyl or tetrazolylmethylene, or --CO₂ R⁹ or--CH₂ CO₂ X⁹ or --CONR¹⁰ R¹¹ or nitrile wherein

R⁹ is lower alkyl and

R¹⁰ and R¹¹ are hydrogen, lower alkyl, alkylsulfonyl or arylsulfonyl ortogether are an alkylene chain to form a ring,

n represents a number 1 to 10,

m represents a number 0 to 7,

T and Z are identical or different and represent oxygen or a direct bondand

R², R³, R⁸ are identical or different and represent hydrogen, alkyl,alkoxy, halogen, trifluoromethyl, trifluoromethoxy, cyano or nitro

and their salts have been found.

Surprisingly the substances according to the invention are potentleukotriene antagonists and can be used for the therapeutic treatment ofhumans and animals.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the formula (I) according to the invention can also bein the form of their salts. In general, the salts which may be mentionedin this context are physiological ones with organic or inorganic bases.The intermediate esters or mixed ester acids or salts thereof can alsobe used as active compounds in medicaments.

Physiologically acceptable salts are preferred within the scope of thepresent invention. Physiologically acceptable salts of the alkenoic acidderivatives can be metal or ammonium salts of the substances accordingto the invention which have free carboxyl groups. Examples of thosewhich are particularly preferred are sodium, potassium, magnesium orcalcium salts, as well as ammonium salts which are derived from ammoniaor organic amines such as, for example, ethylamine, di- ortriethylamine, di- or triethanolamine, dicyclohexylamine,dimethylaminoethanol, arginine or ethylenediamine.

Double bonds can be either cis- or trans-configurated. The carbonbetween X and Y can be either R- or S-configurated.

In general, alkyl represents straight-chain or a branched hydrocarbonradical having 1 to about 12 carbon atoms. Lower alkyl having 1 to about6 carbon atoms is preferred. Examples which may be mentioned are methyl,ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl,isohexyl, heptyl, isoheptyl, octyl and isooctyl.

In general, cycloalkyl represents a cyclic hydrocarbon radical having 5to 8 carbon atoms. The cyclopentane and the cyclohexane ring arepreferred. Examples which may be mentioned are cyclopentyl, cyclohexyl,cycloheptyl and cyclooctyl.

Alkoxy generally represents a straight-chain or branched hydrocarbonradical which has 1 to 12 carbon atoms and is bonded via an oxygen atom.Lower alkoxy having 1 to 6 carbon atoms is preferred. An alkoxy radicalhaving 1 to 4 carbon atoms is particularly preferred. Examples which maybe mentioned are methoxy, ethoxy, propoxy, isopropoxy, butoxy,isobutoxy, pentoxy, isopentoxy, hexoxy, isohexoxy, heptoxy, isoheptoxy,octoxy or isooctoxy.

In general, aryl represents an aromatic radical having 6 to 12 carbonatoms. Preferred aryl radicals are phenyl, naphthyl and biphenyl.

Halogen generally represents fluorine, chlorine, bromine or iodine,preferably fluorine, chlorine or bromine. Halogen particularlypreferably represents fluorine or chlorine.

Sulfoxide may be represented by the formula ##STR3##

Sulfone may be represented by the formula ##STR4##

Preferred compounds of the general formula (I) are those, in which

X and Y are identical or different and represent sulfur, sulfoxide,sulfone, a methylene group, --SCH₂ --, oxygen, an ethylene group or adirect bond,

W represents --CH═CH-- or --CH₂ CH₂ --

o represents a number 1 to 4,

n represents a number 2 to 7,

m represents a number 0 to 3,

T and Z are identical or different and represent oxygen or a direct bondand

R², R³, R⁸ are identical or different and represent hydrogen, loweralkyl, lower alkoxy, fluorine, chlorine or trifluoromethyl,

A and B are identical or different and represent carboxyl,carboxylmethylene, tetrazolyl or tetrazolylmethylene or --CO₂ R⁹ or--CH₂ CO₂ R⁹ or --CONR¹⁰ R¹¹ or nitrile wherein

R⁹ is lower alkyl and

R¹⁰ and R¹¹ are hydrogen, lower alkyl, alkylsulfonyl or arylsulfonyl,

and their salts.

Particularly preferred compounds of the general formula (I) are those inwhich

X represents sulfur or a methylene group,

Y represents sulfur, a methylene group, SCH₂ or a direct bond,

W represents --CH═CH--,

R⁸ and R³ represent H,

R² represents H or fluorine

o represents a number 1, 2, 3 or 4

n represents a number 2, 3, 4, 5 or 6,

m represents a number 0, 1, 2 or 3

T represents oxygen or a direct bond

Z represents oxygen or a direct bond

A represents carboxyl or ester thereof

B represents para carboxyl or ester thereof

and their salts.

Examples which may be mentioned are the following alkenoic acidderivatives:

6-(4-Carboxybenzyl)-9-[3-(3-phenoxypropoxy)phenyl]-7(Z)-nonenoic acid

6-(4-Carboxybenzyl)-10-[4-(3-phenoxypropoxy)phenyl]-7(Z)-decenoic acid

6-(4-Carboxybenzyl)-9-[4-(4-phenoxybutoxy)phenyl]-7(Z)-nonenoic acid

6-(4-Carboxybutoxy)-9-[4-(4-phenoxybutoxy)phenyl]-5-thia-7(Z)-nonenoicacid

6-(4-Carboxybenzyl)-10-[4-(3-phenoxypropoxy)phenyl]-5-thia-7(Z)-decenoicacid

6-(4-Carboxybenzyl)-9-[3-(3-phenoxypropoxy)phenyl]-5-thia-7(Z)-nonenoicacid

6-(4-Carboxybenzyl)-9-[2-(3-phenoxypropoxy)phenyl]-5-thia-7(Z)-nonenoicacid

6-(4-Carboxybenzyl)-9-[4-(3-phenoxypropoxy)phenyl]-5-thia-7(Z)-nonenoicacid

6-(4-Carboxybenzyl)-9-[2-(3-phenoxypropoxy)phenyl]-7-(Z)-nonenoic acid

6-(4-Carboxybenzyl)-9-[4-3-phenoxypropoxy)phenyl]-7(Z)-nonenoic acid

6-(4-Carboxybenzyl)-8-[4-(4-phenoxybutoxy)phenyl]-7(E)-octenoic acid

6-(4-Carboxybenzyl)-8-[4-(4-phenoxybutoxy)phenyl]-7(Z)-octenoic acid

6-(4-Carboxybenzyl)-8-[3-(4-phenoxybutoxy)phenyl]-7(Z)-octenoic acid

6-(4-Carboxybenzyl)-8-[3-(4-phenoxybutoxy)phenyl]-7(E)-octenoic acid

6-(4-Carboxybenzyl)-8-[4-(4-phenoxybutoxy)phenyl]-5-thia-7(E)-octenoicacid

6-(4-Carboxybenzyl)-8-[4-(4-phenoxybutoxy)phenyl]-5-thia-7(Z)-octenoicacid

6-(4-Carboxybenzyl)-8-[4-(4-phenoxybutoxy)phenyl]-5-thia-7(Z)-octenoicacid

6-(4-Carboxybenzyl)-8-[3-(4-phenoxybutoxy)phenyl]-5-thia-7(Z)-octenoicacid

6-(4-Carboxybenzyl)-8-[3-(4-phenoxybutoxy)phenyl]-5-thia-7(E)-octenoicacid

6-(4-Carboxybenzyl)-8-[2-(4-phenoxybutoxy)phenyl]-5-thia-7(E)-octenoicacid

6-(4-Carboxybenzyl)-8-[2-(4-phenoxybutoxy)phenyl]-7(E)-octenoic acid

6-(4-Carboxyphenyl)-9-[4-(3-phenoxypropoxy)phenyl]-7(Z)-nonenoic acid

6-(4-Carboxybenzyl)-8-[3-(5-phenoxypentyl)phenyl]-7(E)-octenoic acid

6-(4-Carboxybenzyl)-8-[3-(5-phenoxypentyl)phenyl]-7(Z)-octenoic acid

6-(4-Carboxybenzyl)-8-[4-(5-phenoxypentyl)phenyl]-7(E)-octenoic acid

6-(4-Carboxybenzyl)-9-(3-[5-phenylpentyl]-phenyl)-7(Z)-nonenoic acid

6-(4-Carboxybenzyl)-9-(3-[4-phenoxybutyl]-phenyl)-7(Z)-nonenoic acid

6-(4-Carboxybenzyl)-9-(3-[3-(4-fluorophenoxy)-propoxy]benzyl-7(Z)-nonenoicacid

Furthermore a process for the preparation of the alkenoic acidderivatives, of the formula (I) ##STR5## in which R², T, Z, R³, W, X, A,B, R⁸, n, m, o and Y have the above mentioned meanings

has been found, which is characterized in that aldehydes of the generalformula (II) ##STR6## in which X, Y, o and R⁸ have the above mentionedmeanings and

A and B are identical or different and represent CO₂ R⁹ or CH₂ CO₂ R⁹ orCONR¹⁰ R¹¹ or nitrile wherein R⁹ represents lower alkyl and R¹⁰ and R¹¹represent lower alkyl, a methylene chain or H,

are reacted with phosphorus compounds of the general formula (III)

    R.sup.1 --CH.sub.2 --U                                     (III)

in which

R¹ is ##STR7## in which R², T, n, Z, R³ and m have the above mentionedmeanings and

U represents a group of the formula ##STR8## where R⁶ and R⁷ areidentical or different and denote alkyl or phenyl and

V denotes a halide anion or a tosylate anion

in inert solvents in the presence of bases, whereby the esters are thenoptionally hydrolyzed or partially hydrolyzed. Halide anions arepreferably chlorides, bromides or iodides.

Suitable inert solvents for the process according to the invention arethose conventional organic solvents which do not change under thereaction conditions. They preferably include ethers such as diethylether, butyl methyl ether, dioxane, tetrahydrofuran, glycol dimethylether or diethylene glycol dimethyl ether, or hydrocarbons such asbenzene, toluene, xylene or petroleum fractions, or amides such asdimethylformamide or hexamethylphosphoric triamide, or1,3-dimethyl-imidazolidin-2-one, 1,3-dimethyl-tetrahydro-pyridin-2-oneor dimethyl sulphoxide. It is likewise possible to use mixtures of thesolvents mentioned.

Suitable bases are the conventional basic compounds for basic reactions.These preferably include alkali metal hydrides such as, for example,sodium hydride or potassium hydride, or alkali metal alcoholates such assodium methanolate, sodium ethanolate, potassium methanolate, potassiumethanolate or potassium tert.butylate, or amides such as sodium amide orlithium diisopropylamide, or organolithium compounds such asphenyllithium, butyllithium or methyllithium or sodiumhexamethyldisilazane.

The choice of solvent or base depends on the stability, sensitivity tohydrolysis or CH acidity of the respective phophorus compound. Etherssuch as diethyl ether, tetrahydrofuran, dimethoxyethane or dioxane,together with a co-solvent such as dimethylformamide or 1,3-dimethyltetrahydropyridin-2-one or 1,3-dimethylimidazolid-2-one, areparticularly preferably used as solvent. Alkali metal alcoholates suchas potassium tert.butylate, or organollithium compounds such asphenyllithium or butyllithium or sodium hydride are particularlypreferably used as bases.

The reaction is generally carried out in the temperature range from -80°C. to +70° C., preferably from -80° C. to +20° C.

The reaction may be carried out at atmospheric, elevated or reducedpressure (for example, 0.5 to 5 bar). In general, the reaction iscarried out at atmospheric pressure.

When carrying out the reaction the phosphorus compounds are generallyemployed in an amount of from 1 to 2 moles, preferably in molar amounts,relative to 1 mole of the aldehyde. The bases are generally employed inan amount of from 1 to 5, preferably from 1 to 2 moles, relative to 1mole of the phosphorus compound.

The process according to the invention can be carried out, for example,by adding the base and then the aldehyde, if appropriate in a suitablesolvent, to the phosphorus compounds dissolved or suspended in asuitable solvent, and if appropriate, heating the mixture. The workingup is effected in a conventional manner by extraction, chromatographyand/or crystallization.

When carrying out the process according to the invention, it is likewisepossible to employ the appropriate phosphoranes [(R⁶)₃ P═CHR], whichhave previously been prepared from the appropriate phosphonium salts andbases in a separate reaction, directly in place of the phosphonium salts(W=--P(R⁶)₃.sup.⊕ T.sup.⊖). However, it has proven favorable to carryout the reaction with the phosphorus compounds in the presence of basesas a one-pot process.

The phosphorus compounds of the general formula (IIIa)

    R'--CH.sub.2 --U                                           (IIIa)

where

R¹ and U have the abovementioned meanings

are new.

Depending on the meaning of Z, the compounds can be prepared asillustrated, for example, by the following equations: ##STR9##

PROCESS A First Variant

In the first reaction step [A] of this variant the acetylene compounds(IV) are reacted with a bromobenzaldehyde (V) in solvents such astriethylamine, acetonitrile, pyridine or mixtures thereof, preferably intriethylamine, in the presence of copper (I) salts and palladium (O)compounds preferably in the presence of copper (I) halides, such as forexample copper iodide andbis-(triphenylphosphine)-palladium(II)-chloride, in a temperature rangeof from -40° C. to +80° C., preferably from 0° C. to +40° C. In thesecond reaction step [B] the formyl compound (VI) is reduced to thehydroxyl compounds (VII) in solvents such as alcohols, for example,methanol, ethanol, propanol or isopropanol, or ethers such as diethylether, tetrahydrofuran or dioxane, or in bases such as triethylamine,pyridine or dimethylformamide, or water or in mixtures of the statedsolvents, using complex hydrides, such as, for example, boron hydridesor aluminium hydrides, preferably sodium hydridoborate or lithiumaluminium hydride as reducing agents, in a temperature range of from-40° C. to +60° C., preferably from 0° C. to +40° C.

In the third reaction step [C] the compounds (VII) are hydrogenated ininert solvents such as alcohols, for example, methanol, ethanol,propanol or isopropanol, or hydrocarbons such as benzene, toluene orxylene, or in others such as diethyl ether or tetrahydrofuran, or ethylacetate, preferably in methanol, in the presence of noble metalcatalysts such as palladium or platinum, in a temperature range of from-30° C. to +80° C., preferably from 0° C. to +40° C., under a pressureof from 1 bar to 50 bars, preferably from 1 bar to 20 bars. Steps B andC may be reversed in order. In the fourth step [D] the hydrogenatedcompounds (VIII) are brominated by reacting them with brominating agentssuch as for example phosphorus tribromide, sulphonyl bromide, hydrogenbromide or tetrabromethane/triphenylphosphine in inert solvents, such asether, for example diethyl ether or tetrahydrofuran, or hydrocarbonssuch as benzene or toluene or preferably chlorinated hydrocarbons suchas methylene chloride or chloroform, in a temperature range of from -20°C. to +60° C., preferably from 0° C. to +40° C. In the fifth reactionstep [E] the brominated compounds (IX) are reacted withtriphenylphosphine in inert solvents such as acetonitrile orhydrocarbons such as benzene, toluene or xylene, or benzonitrile ordimethylformamide or dimethyl sulphoxide or an alcohol such as methanol,ethanol, propanol or isopropanol or without solvent, in a temperaturerange of from 0° C. to +200° C., preferably from +20° C. to +180° C., togive the phosphonium salts (X). ##STR10##

In the first reaction step [1] are brominated by reacting them withbrominating agents such as for example those listed in Process A--Firstvariant--step D.

[B] Bromides (2) are reacted with triphenylphosphine as in ProcessA--First variant--step E.

[C] Is a process generating the reactive phosphorane as detailed earlierin the reaction of compound III and reacting it with a bromobenzaldehydeof the desired substitution pattern.

[D] Where X denotes a direct bond. Reaction of the bromide (4) with asuitable base preferably t-butyllithium in an inert solvent(tetrahydrofuran) at low temperature followed by addition of a suitableelectrophile such as paraformaldehyde (V, p=1) or ethylene oxide (V,p=2) gives the primary alcohols.

Alternatively X denotes a triple bond and reaction with an optionallyprotected hydroxyalkyne such as the tetrahydropyranyl ether ofpropargylalcohol using the process step [A] of process A--First variant.

[E] Is a hydrogenation as described in step C of process A--FirstVariant.

[F] and [G] are identical to [A] and [B] respectively. ##STR11##

PROCESS VARIANT B

In the first reaction step [A] of this variant the bromine compounds(XI) are reacted with the phenols (XII) in suitable solvents such aswater, or alcohols such as for example methanol, ethanol, propanol orisopropanol, or ethers such as diethyl ether, tetrahydrofuran, dioxaneor dimethyloxyethane, or dimethylformamide or dimethylsulphoxide,preferably in isopropanol, in the presence of bases such as alkali metalhydroxides, carbonates or alcoholates, such as, for example, sodiumcarbonate, potassium carbonate, sodium hydroxide, potassium hydroxide,sodium ethanolate or potassium tert. butylate, in a temperature range offrom 0° C. to +200° C., preferably from +20° C. to 180° C. In the secondstep [B] the phenyl ethers XIII are reacted with tosyl chloride in inertsolvents such as ether, for example diethylether, tetrahydrofuran ordioxane, or hydrocarbons such as benzene or toluene, or chlorinatedhydrocarbons such as chloroform or methylene chloride, or ethylacetate,acetone or acetonitrile, preferably in methylene chloride, in thepresence of bases such as triethylamine, diisopropylamine, pyridine ordimethylaminopyridine, preferably in the presence of pyridine, in atemperature range of from -30° C. to +50° C., preferably from -10° C. to+30° C. In the third reaction step [C] the tosyl compounds (XIV) arereacted with triphenylphosphine in suitable solvents such ashydrocarbons, for example, benzene or toluene, benzonitrile,acetonitrile, dimethylformamide or dimethylsulphoxide or withoutsolvent, preferably in acetonitrile, in a temperature range from 0° C.to +200° C., preferably from +20° C. to +180° C., to give thephosphonium salts (XV).

The aldehydes of the general formula (II) are new.

Depending on the meaning of X and Y they can be prepared as illustratedfor example by the following equations: ##STR12##

PROCESS VARIANT C

In the first reaction step [A] of this variant the ketone (XVI) isreacted with 4-chloromethylbenzoic acid esters in inert solvents such asether, for example, diethylether, tetrahydrofuran or dioxane, ordimethylformamide, or dimethylsulphoxide, or mixtures thereof,preferably in dimethylformamide, in the presence of bases such as alkalimetal hydrides, amides or alcoholates, such as sodium hydride, potassiumhydride, lithium diisopropylamide, potassium ethylate, sodium ethylate,potassium methylate or potassium tert. butylate, preferably in thepresence of sodium hydride, in a temperature range of from -40° C. to+60° C., preferably from -20° C. to +30° C. In the second reaction step[B] the cyclohexanones (XVIII) are reacted in suitable solvents such asdimethylformamide or alcohols, for example, methanol, ethanol, propanolor isopropanol, or water, or mixtures therefore, preferably indimethylformamide or ethanol, in the presence of bases such as alkalimetal hydroxides, alkali metal carbonates of alkali metal alcoholates,such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodiummethanolate, sodium ethanolate, potassium ethanolate or potassium tert.butanolate, preferably in the presence of potassium tert. butanolate, ina temperature range of from 0° C. to +150° C., preferably from +20° C.to +100° C., to give the triesters XVIII. In the third reaction step [C]the triesters (XVIII) are saponified in suitable solvents such asalcohols such as, for example, methanol, ethanol, propanol orisopropanol, or ethers, such as methyl ether, tetrahydrofuran ordioxane, or chlorinated hydrocarbons such as methylene chloride orchloroform, or carboxylic acids such as acetic acid or trifluoroaceticacid or mixtures thereof, preferably in trifluoroacetic acid, in thepresence of acids such as mineral acids, for example hydrochloric acid,hydrobromic acid or sulphuric acid, or carboxylic acids such as aceticacid or trifluoroacetic acid, preferably in the presence of acetic acid,particularly preferably using trifluoroacetic acid, both as the solventand the acid, in a temperature range of from -20° C. to +60° C.,preferably from 0° C. to +30° C., to give the carboxylic acids XIX. Inthe fourth step [D] the carboxylic acids (XIX) are reduced in suitablesolvents such as ethers, for example, diethylether, tetrahydrofuran ordioxane, or chlorinated hydrocarbons such as methylene chloride orchloroform, or mixtures thereof, preferably in tetrahydrofuran, usingboron compounds as reducing agents, such as, for example, borane or theborane dimethylsulphide complex, in a temperature range of from -40° C.to +60° C., preferably from -20° C. to +30° C. to give the hydroxylcompounds (XX). In the fifth reaction step [E] the hydroxy compounds(XX) are oxidized in suitable solvents such as ether, for example,diethyl ether, dioxane or tetrahydrofuran, or chlorinated hydrocarbonssuch as methylene chloride or chloroform, or dimethyl sulphoxide, ormixtures thereof, preferably in dichloromethane, using oxidizing agentssuch as pyridinium chlorochromate, chromium (VI) salts, dimethylsulphoxide/pyridine/SO₃, preferably using pyridinium chlorochromate, ifappropriate in the presence of bases such as triethylamine, diisopropylamine, pyridine or dimethylaminopyridine, preferably in thepresence of triethylamine, in a temperature range of from -20° C. to+60° C., preferably from 0° C. to +30° C., to give the aldehydes (XXI).##STR13##

PROCESS VARIANT D

In the first reaction step [A] of this variant the benzoic acid mixture(XXII) is converted into the ester (XXIII) in suitable solvents such asalcohols, for example, methanol, ethanol, propanol or isopropanol, orwater, or mixtures thereof, preferably in methanol, in the presence ofacids such as mineral acids, for example, hydrochloric acid, hydrobromicacid or sulphuric acid or carboxylic acids such as acetic acid ortrifluoroacetic acid, or preferably in the presence of thionyl chloride,in a temperature range of from -40° C. to +60° C., preferably from -20°C. to +40° C. In the second reaction step [B] the esters (XXIII) areoxidized in suitable solvents such as ether, for example, diethyl ether,tetrahydrofuran or dioxane, or dimethyl sulphoxide, or chlorinatedhydrocarbons such as methylene chloride or chloroform, or mixturesthereof, preferably in methylene chloride, using oxidizing agents suchas bromine (VI) salts, pyridinium chlorochromate, dimethylsulphoxide/oxalyl chloride or dimethyl sulphoxide/pyridine/SO₃,preferably using dimethyl sulphoxide/oxalyl chloride as oxidizingagents, in the presence of bases such as triethylamine,diisopropylamine, pyridine or dimethylaminopyridine, preferably in thepresence of triethylamine, in a temperature range of from -80° C. to+40° C., preferably from -60° C. to +20° C. to give the aldehydes(XXIV), In the third reaction step [C] the aldehydes (XXIV) areconverted into the silicon compounds (XXV) in suitable solvents such ashydrocarbons such as benzene, toluene or xylene, or dimethyl sulphoxide,or amides such as dimethyl formamide or hexamethylphosphoric acidtriamide, or mixtures thereof, preferably in dimethyl formamide, in thepresence of bases such as triethylamine, diisopropylamine, pyridine ordimethylaminopyridine, preferably in the presence of triethylamine, in atemperature range of from 0° C. to +200° C., preferably from +20° C. to+180° C. In the fourth reaction step these silicon compounds (XXV) areconverted with 4,4'-dithiodibutyric acid dimethyl ester or3,3'-dithiodipropanoic acid dimethyl ester in the presence of sulfurylchloride or chlorine or bromine into the aldehydes (XVI) in suitablesolvents such as ether, for example, diethylether, tetrahydrofuran ordioxane, or hydrocarbons such as benzene or toluene, or chlorinatedhydrocarbons such as methylene chloride or chloroform, or mixturesthereof, preferably in methylene chloride, if appropriate in thepresence of bases, such as triethylamine or diisopropylamine orpyridine, in a temperature range of from -80° C. to +20° C., preferablyfrom -70° C. to 0° C. ##STR14##

PROCESS VARIANT E

In this variant benzoic acid (XXVII) is reacted in suitable solventssuch as ether, for example, diethyl ether, tetrahydrofuran, dioxane,diethylene glycol monomethylether or diethylene glycol diethyl ether, oramides such as dimethyl formamide or hexamethylphosphoric acid triamide,1,3-dimethylimidazolidin-2-one or 1,3-dimethyltetrahydropyridin-2-one,or mixtures thereof, preferably in tetrahydrofuran, in the presence oforganometallic compounds as the base, such as, for example, organiclithium, sodium or potassium compounds, preferably butyllithium,methyllithium, phenyllithium, sodium naphthalide, potassium naphthalide,lithium diisopropylamide or lithium hexamethyldisilazane, preferably inthe presence of lithium diisopropylamide as the base, in a temperaturerange of from -80° C. to +60° C., preferably from -50° C. to +30° C., togive the compounds (XVIII), which are then reduced in the secondreaction step [B] in suitable solvents such as ether, for example,diethyl ether, tetrahydrofuran or dioxane, or chlorinated hydrocarbonssuch as methylene chloride or chloroform, or mixtures thereof,preferably in tetrahydrofuran, using boranes as reducing agents,preferably using borane or borane dimethyl sulphide complex, in atemperature range of from -40° C. to +60° C., preferably from -20° C. to+30° C., to give the hydroxy compounds (XXIX). In the third reactionstep [C] the hydroxy compounds (XXIX) are oxidized in suitable solventssuch as ether, for example, diethyl ether, tetrahydrofuran or dioxane,or chlorinated hydrocarbons such as methylene chloride or chloroform, ordimethyl sulphoxide, or mixtures thereof, preferably in dichloromethane,using oxidizing agents such as chromium VI salts, pyridiniumchlorochromate, dimethyl sulphoxide/oxalyl chloride or dimethylsulphoxide/pyridine/SO₃, preferably using pyridinium chlorochromate asthe oxidizing agent, if appropriate in the presence of bases such astriethylamine, diisopropylamine or pyridine, preferably in the presenceof triethylamine, in a temperature range of from -80° C. to +60° C.,preferably from -60° C. to +30° C., to give the aldehydes (XXX).##STR15##

PROCESS VARIANT F (X'=CH₂ or direct bond, Y'=SO₂ or X'=SO₂, Y'=CH₂ ordirect bond)

In this variant acid (XXXI) is reacted in suitable solvents such asalcohols, water, acetone or acetonitrile with an oxidizing agent such ashydrogen peroxide, nitric acid, peracids, oxygen, ozone, organicperacids, potassium permangerate, potassium persulfate, sodiumhypochlorite, hypochlorous acid, rutherium tetroxide, oxides ofnitrogen, anodic oxidation or with special mixture such as oxone in ausual temperature range of from -20° C. to +30° C., although forspecially unsuitable substances even lower temperature ranges (-78° C.)may be necessary. The product of this process is sulfone (XXXII, X' orY'=SO₂).

PROCESS VARIANT G (X'=CH₂ or direct bond, Y'=SO or X'=SO, Y'=CH₂ ordirect bond)

In this variant acid (XXXI) is reacted as in variant E, but with lessoxidizing agent and/or at a lower temperature or with oxidizing agentssuch as hydroperoxides, manganese dioxide, selenium dioxide, peracids,chromic acid or iodosobenzene. The product of this process is sulfoxide(XXXII, X' or Y'=SO). ##STR16## In this process acid XXXIII is reactedin suitable solvents such as alcohols, water, benzene, toluene, etherssuch as diethylether, tetrahydrofuran, dioxane or esters such as ethylacetate or hydrocarbons such as hexane or amines such as triethylamineor ammonia with a suitable reducing agent such as hydrogen in thepresence of a metal catalyst such as oxides or soluble complexes ofpaladium, platinum, rutherium or nickel or with a metal such as lithiumor sodium or with hydrazine or aryl aralkoxy substituted hydrazines. Theproduct of this reaction is acid (XXXIV) in which W or the genericstructure (I) is --CH₂ CH₂ --. The usual temperature range for thisprocess is from -20° C. to +30° C. ##STR17##

This process variant is directly analogous to that described in processD and offers an alternative to process C for the case where Y=S.However, it is applicable for rather more than o=3 or 4 as in process C.

The three steps are as described:

[A] is equivalent to step E of process C

[B] is equivalent to step C of process D when R=trimethylsilyl.

Alternatively R=alkyl e.g. methyl and step B is performed by addition ofthe aldehyde to a solution of an alkoxymethylene ylide. The latter isgenerated from an alkoxymethylene triphenylphosphonium salt as describedearlier for the reaction of compound III with II.

[C] is equivalent to step D or process D. ##STR18##

These variants of a similar process offer two routes to aldehydes XLIIIor XLVII.

Step A is identical in both processes namely the reaction of an aldehydeXL or XLIV with a dialkylaminohydrazine such as dimethylhydrazine (E. J.Corey and D. Enders, Chem. Ber., 111, 1337, 1363, (1978), or (R) (or(S)) 1-amino-2-methoxymethylpyrrolidine (D. Enders et al, Org. Syn., 65,183, (1987)). The use of these chiral hydrazones (RAMP or SAMP) allowsthe subsequent step to proceed with virtually completeenantioselectivity so that the product of step B may be a singleenantiomer. Thus obviating the need for resolution of products such asXLIII or XLVII by other means. Step A is best achieved by mixing of thealdehyde and hydrazine in the absence of solvent and heating to 60°-70°C. for an appropriate time (1 day) under an inert atmosphere.

Step B is effected in suitably inert solvents such as diethylether ortetrahydrofuran at reduced temperature, preferably 0° C., with anappropriate organometallic base such as butyllithium or lithiumdiisopropylamide followed by the addition of an appropriate electrophile(RO₂ C(CH₂)_(n) Hal, R₆ O₂ C C₆ H₄ CH₂ Hal or RO₂ C C₆ H₄ SCl) to givethe alkylated product XLII or XLVI.

Step C is an oxidative cleavage of the hydrazones to give the aldehydesXLIII or XLVII using e.g. ozone in a suitable solvent (dichloromethane)at low temperature (-78° C.) when the chiral hydrazones are used. Thedimethyl hydrazones may be cleaved with sodium periodate in aqueoussolution or by methylation with methyl iodide followed by addition ofacid. ##STR19##

These processes illustrate two ways of preparing an aldehyde LI or LVIIwhere X=oxygen.

In the first instance an ω-oxoalkanoate (XLVIII) [or as ω-oxoalkenoateis reacted with sulphonium methylide (E. J. Corey et al, J. Am. Chem.Soc., 87, 1353, (1965))] in a suitable inert solvent to give an epoxideXLIX.

The epoxide undergoes nucleophilic ring opening with a phenol in avariety of solvents such as methanol to give two regioisomers from whichthe desired isomer L is readily obtained by chromatography. The yieldand ratio of the two isomers may be manipulated by altering the solventand by use of a variety of catalysts.

Step C is a simple oxidation as already detailed in process E step C.

Alternatively a diol LII is monoprotected with a suitable protectinggroup such as tetrahydropyranylether, t-butyldimethylsilyl ether,tert-butyldiphenylsilylether to give a secondary alcohol LIII. Step Binvolves the conversion of the alcohol into a suitable leaving group Xsuch as tosylate or halide (preferably bromide or iodide) by methodsalready detailed in other processes.

Step C involves replacement of the leaving group by a phenoxy groupessentially as described in Step A of process B.

Step D involves selective removal of the protecting group P by a mildmethod appropriate to the given P. Step E is a simple oxidation asabove.

PROCESS N (B=ortho or meta CO₂ H or ortho or meta or para CH₂ CO₂ H,CHN₄, CONR¹⁰ R¹¹)

All the processes illustrate the preparation of β-disubstitutedaldehydes with a para alkoxycarbonyl group. Clearly in all these casesit is possible to use a meta, or ortho, disubstituted benzoate insteadof the para disubstituted compound.

Similarly the alkoxycarbonyl group can be replaced by analkoxycarbonylmethyl group to give a product where A=CH₂ CO₂ H. Theintroduction of a tetrazole group is best effected by use of a suitablemonosubstituted benzonitrile to give intermediates where A=nitrile. Thisis then converted to a tetrazole by reaction with sodium azide in thepresence of a salt of a suitable tertiary base (triethylamine ormorpholine hydrochloride) in an inert solvent (dimethylformamide) atelevated temperature.

The introduction of amides or sulphonamides is best effected by ajudicious choice of esters at the aromatic and aliphatic carboxyl groupsso that either carboxyl group may be selectively liberated. The saidcarboxyl group can then be reacted with an aryl, or alkyl, sulphonamidein the presence of a dimide such as dicyclohexylcarbodiimide in asuitably inert solvent. Alternatively the carboxylic acid can besuitably activated by e.g. reaction with diphenyl phosphinic chlorideand then treated with the desired amine to give an amide.

The compounds of the general formula (I) according to the invention havepharmacological properties and in particular they are antagonists forleucotriene diseases: asthma, circulatory diseases, respiratorydiseases. They can therefore be used as pharmaceuticals.

The new active compounds can be converted in a known manner into thecustomary formulations, such as tablets, dragees, pills, granules,aerosols, syrups, capsules, emulsions, suspensions and solutions, usinginert non-toxic, pharmaceutically suitable excipients or solvents. Thetherapeutically active compound should in each case be present in aconcentration of about 0.5 to 98% preferably 1 to 90%, by weight of thetotal mixture, that is to say in amounts which suffice to achieve thedosage range indicated.

The formulations are prepared, for example, by extending the activecompounds with solvents and/or excipients, optionally with the use ofemulsifiers and/or dispersing agents, and, for example, when using wateras a diluent, organic solvents can optionally be used as auxiliarysolvents.

Examples of auxiliary substances which may be mentioned are: water,non-toxic organic solvents, such as paraffins (for example, petroleumfractions), vegetable oils (for example, groundnut oil/sesame oil),alcohols (for example, ethyl alcohol and glycerol), excipients, such as,for example, ground natural mineral (for example, kaolins, aluminas,talc and chalk), ground synthetic mineral (for example, highly dispersesilica and silicates) and sugars (for example, sucrose, lactose andglucose), emulsifiers (for example, polyoxyethylene fatty acid esters),polyoxyethylene fatty alcohol ethers (for example, lignin, sulphitewaste liquors, methylcellulose starch and polyvinylpyrrolidone) andlubricants (for example, magnesium stearate, talc, stearic acid andsodium sulphate).

Administration is effected in the customary manner, preferably orally,by inhalation or parenterally, particularly perlingually orintravenously. In the case of oral use, the tablets can, of course, alsocontain, in addition to the excipients mentioned, additives such assodium citrate, calcium carbonate and dicalcium phosphate, together withvarious additional substances, such as starch, preferably potato starch,gelatine and the like. Furthermore, lubricants, such as magnesiumstearate, sodium lauryl sulphate and talc, can be used concomitantly inthe production of tablets. In the case of aqueous suspensions, theactive compounds can be mixed with various flavor-improving agents orcolorants in addition to the abovementioned auxiliary substances.

In the case of parenteral use, solutions of the active compounds, usingsuitable liquid excipients, can be employed.

In general, it has proved advantageous, in the case of intravenousadministration, to administer amounts of about 0.001 to 1 mg/kg,preferably about 0.01 to 0.5 mg/kg, of body weight to achieve effectiveresults, and in the case of oral administration, the dosage is about0.01 to 20 mg/kg, preferably 0.1 to 10 mg/kg of body weight.

Nevertheless, it may be necessary, under certain circumstances, todeviate from the amounts mentioned, and in particular to do so as afunction of the body weight or of the nature of the administrationmethod, of the individual reaction towards the medicament, the nature ofits formation, and the time or interval over which the administrationtakes place. Thus, it can in some cases suffice to use the minimumamount, whereas in other cases the upper limit mentioned must beexceeded. In the case of administration of larger amounts, it may beadvisable to divide these into several individual administrations overthe course of the day.

PREPARATION EXAMPLES EXAMPLE 1 5-Phenoxy-1-pentyne ##STR20##

A 2.81 g (58.5 mmol) portion of sodium hydride (50% in oil) was washedwith dry hexane and then dried in vacuo. The residue was slurried in 20ml of anhydrous tetrahydrofuran under argon with 0° C. bath cooling anda solution of 5.51 g (58.5 mmol) of phenol in 20 ml tetrahydrofuran wasadded dropwise. After vigorous gas evolution had ceased a 10 ml portionof anhydrous hexamethylphosphoryltriamide was added followed by asolution of 4.85 g (47.3 mmol) of 5-chloro-1-pentyne in 7 mltetrahydrofuran. The resulting grey solution was refluxed for 3 days.The resulting mixture was cooled, diluted with hexane and washed withwater. It was then washed with aqueous potassium carbonate to remove theresidual phenol. The resulting solution was dried over magnesium sulfateand evaporated in vacuo. The orange oily residue was distilled using anaspirator vacuum to yield 6.48 g pure product as a colorless oil.

bp.: 115°-118° C. (23 mm).

Yield: 86% of theory.

TLC-R_(f) : 0.62 (methylenechloride)

NMR (CDCl₃, 300 MHz): 1.94-2.06 [3] m, 2.35-2.44 [2] m, 4.05 [2] t, J=7Hz, 6.86-6.97 [3] m, 7.1-7.3 [2] m.

EXAMPLE 2 4-(5-Phenoxy-1-pentyn-1-yl)benzaldehyde ##STR21##

A solution of 2.08 g (13.0 mmol) of 5-phenoxy-1-pentyne and 2.00 g(10.81 mmol) of 4-bromobenzaldehyde in 7.0 ml of dry triethylamine wasstirred under argon as 0.758 g (1.08 mmol) ofbis(triphenylphosphine)palladium(II)chloride was added followed by 103mg (0.54 mmol) of copper(I)iodide. The reaction mixture turned dark andbecame warmed as it was stirred over 15 minutes, It was then stirredovernight under argon. It was diluted with ethyl acetate and then washedwith 2% sulfuric acid, then water and finally saturated sodium chloride.The resulting solution was dried over a mixture of magnesium sulfate andNorite (decolorizing active carbon), and then filtered and evaporated invacuo. The orange solid residue was dissolved in minimum benzene andchromatographed on silica gel using 3% ethyl acetate in hexane elutionto yield 2.21 g of purified product as a tan solid.

Yield: 77% of theory

TLC-R_(f) : 0.36 (ethyl acetate:hexane 2:8)

NMR (CDCl₃, 60 MHz): 2.1 [2] t, J=7, 2.2 [2] t, J=6, 2.7 [2] t, J=7, 4.1[2] t, J=6, 6.8-7.8 [9] m, 10.1 [1] s.

EXAMPLE 3 3-(5-Phenoxy-1-pentyn-1-yl)benzaldehyde ##STR22##

This compound was prepared in a manner analogous to that used for thepara isomer (Example 2). 2.00 g (10.8 mmol) of 3-bromobenzaldehyde,2.087 g (13.0 mmol) of 5-phenoxy-1-pentyne, 7 ml triethylamine, 0.758 g(1.08 mmol) of the palladium compound and 104 mg (0.55 mmol) ofcopper(I)iodide were used. The reaction was found by analysis to beessentially complete after 16 hours ambient temperature. The crudeproduct which was in the form of an orange oil was chromatographed using5% ethyl acetate in hexane to yield 1.924 g of a purified product in theform of a yellow oil.

Yield: 67.3% of theory

TLC-R_(f) : 0.24 (ethyl acetate:hexane 1:9)

NMR (CDCl₃, 60 MHz): 2.1 [2] t, 2.2 [2] t, 4.1 [2] t, J=6, 6.8-7.8 [9]m, 10.1 [1] s.

EXAMPLE 4 4-(5-Phenoxy-1-pentyn-1-yl)benzyl alcohol ##STR23## A solutionof 2.02 g of 4-(5-phenoxy-1-pentyn-1-yl)benzaldehyde in 5 ml of absoluteethanol was stirred with 0° C. bath cooling and 640 mg of sodiumborohydride was added in portions. After stirring for 55 minutes thereaction mixture was quenched by the addition of water and thenevaporated in vacuo. The residue was mixed cautiously with 2% sulfuricacid and extracted twice with ethyl acetate. The combined extracts werewashed with saturated sodium chloride and then a sodium hydrogencarbonate solution. They were dried over magnesiumsulfate and evaporatedin vacuo to yield 2.06 g of the 4-(Phenoxy-1-pentyn-1-yl)-benzyl alcoholwhich was sufficiently pure to use without purification.

Yield: 100% of theory

TLC-R_(f) : 0.12 (ethyl acetate:hexane 2:8)

NMR (CDCl₃, 60 MHz): 2.09 [2] t, 2.12 [2] t, 2.7 [2] t, 4.1 [2] t, J=6Hz, 4.6 [2] s, 6.8-7.4 [9] m.

EXAMPLE 5 3-(5-Phenoxy-1-pentyn-1-yl)benzyl alcohol ##STR24##

This compound was prepared in a manner analogous to that used for thepara isomer (Example 4). Thus 1.924 g of the meta aldehyde were treatedwith 924 mg of sodium borohydride in 50 ml of absolute ethanol at 0° C.for 1 hour. The yield of the 3-(Phenoxy-1-pentyn-1-yl)benzyl alcohol was1.89 g of a yellow oil which was used without further purification.

Yield: 93% of theory

TLC-R_(f) : 0.20 (ethyl acetate:hexane 1:3)

NMR (CDCl₃, 60 Mhz): 2.1 [2] t, 2.14 [2] t, 2.7 [2] t, 4.1 [2] t, J=6,4.6 [2] s, 6.8-7.4 [9] m.

EXAMPLE 6 4-(5-Phenoxypent-1-yl)benzyl alcohol ##STR25## A solution of0.54 g of 4-(5-phenoxy-1-pentyn-1-yl)benzyl alcohol in 100 ml methanolwas treated with 230 mg of 5% palladium on charcoal and 58 PSI hydrogenfor 3.5 hours. The product mixture was filtered using celite and thefiltrate was evaporated in vacuo to yield 0.53 g of the compound in theheading in the form of a light tan solid which was used withoutpurification.

Yield: 98% of theory

NMR (CDCl₃, 60 MHz): 1.6 [6] m, 2.6 [2] t, J=6, 3.2 [1] bs, 3.8 [2] t,J=6, 4.5 [2] s, 6.8-7.3 [9] m.

EXAMPLE 7 3-(5-Phenoxypent-1-yl)benzylalcohol ##STR26##

This compound was prepared in a manner analogous to that used for thepara isomer (Example 6). Thus 1.856 g of3-(5-phenoxy-1-pentyn-1-yl)benzyl alcohol in 100 ml of CH₃ OH wastreated with 333 mg 5% palladium on charcoal and 30 PSI hydrogen for1.25 hours. The product mixture was filtered in the customary mannerthrough celite and the filtrate was evaporated in vacuo to yield 1.89 gof the 3-(5-Phenoxypent-1-yl)benzyl alcohol in the form of a tan solid.

Yield: 100% of theory

NMR (CDCl₃, 60 MHz): 1.6 [6] m, 2.3 [1] bs, 2.6 [2] t, 3.9 [2] t, J=6,4.6 [2] s, 6.8-7.3 [9] m.

EXAMPLE 8 4-(5-Phenoxypent-1-yl)benzyl bromide ##STR27##

A solution of 518 mg (1.92 mmol) 4-(5-phenoxypent-1-yl)benzyl alcohol in3.5 ml of dry methylene chloride was stirred under argon as 826 mg (2.49mmol) of carbon tetrabromide were added followed by 653 mg (2.49 mmol)of triphenylphosphine. The reaction mixture turned yellow and heatedbriefly to reflux. The resulting mixture was stirred under argon for 1.5hours and it was then evaporated in vacuo. The residue was dissolved asfar as possible in a small quantity of warm benzene and chromatographedon silica gel using 2.5% ethyl acetate in hexane elution. The insolublebenzene material was shown by tlc to be a non-usable product. Theproduct which was still not pure was rechromatographed using cyclohexaneto apply the material to the column. 376 mg of a usable pure productplus a smaller amount (56 mg) of a mixed fraction consisting mostly ofthe product along with a more polar contaminant were isolated.

Yield: 59% of theory were obtained.

TLC-R_(f) : 0.33 (ethyl acetate:hexane 5:95)

NMR (CDCl₃, 60 MHz): 1.5-2.0 [6] m, 2.6 [2] t, J=6, 3.9 [2] t, J=6, 4.4[2] s, 6.8-7.4 [9] m.

EXAMPLE 9 2-[4-(4-Phenoxybutoxy)phenyl]ethanol ##STR28## A mixture of10.31 g (45 mmol) of 4-phenoxybutylbromide, 6.22 g (45 mmol) of2-(4-hydroxyphenyl)ethanol and 6.22 g (45 mmol) of pulverized potassiumcarbonate in 45 ml of isopropanol was refluxed for 24 hours. Theresulting mixture was cooled, mixed with water and then extracted threetimes with ethyl acetate. The combined extracts were washed with waterand then with saturated aqueous sodium bicarbonate. They were dried oversodium sulfate and evaporated in vacuo. The residue was chromatographedon 500 g of silica gel (Merck Si60, 0.04-0.063 mm) using methylenechloride/methanol (98:2) as eluent. The product-containing fractionswere evaporated in vacuo to yield 2-[4-(Phenoxybutoxy)phenyl]ethanol inthe form of 9.08 g of crystals.

mp: 102° C.

Yield: 70.5% of theory

TLC-R_(f) : 0.43 (methylenechloride:ethanol 97:3)

NMR (CDCl₃, 300 MHz): 2.0 [4] m, 2.8 [2] tr, J=7 Hz, 3.8 [2] q, J=7 Hz,4.0 [4] q, J=7 Hz, 6.8-7.0 [5] m, 7.15 [2] d, J=8 Hz, 7.3 [2] tr, J=7Hz.

EXAMPLES 10-16

Analogue of Example 9 were prepared:

    ______________________________________                                         ##STR29##                                                                                          mp      yield                                                                              TLC-R.sub.f                                Nr.   n       m       [°C.]                                                                          [%]  Solvent                                    ______________________________________                                        10    3       para 3  56      86.9 0.53                                                                          CH.sub.2 Cl.sub.2 :CH.sub.3 OH                                                95:5                                       11    3       para 2  77      80.8 0.75                                                                          CH.sub.2 Cl.sub.2 :CH.sub.3 OH                                                95:5                                       12    3       meta 2  --      56.6 0.44                                                                          CH.sub.2 Cl.sub.2 :CH.sub.3 OH                                                97:3                                       13    3       ortho 2 --      89.5 0.43                                                                          CH.sub.2 Cl.sub.2 :CH.sub.3 OH                                                97:3                                       14    4       para 1  106     77.0 0.31                                                                          CHCl.sub.3                                 15    4       meta 1  47-48   96.0 0.32                                                                          CHCl.sub.3                                 16    4       ortho 1 33-34   74.0 0.51                                                                          CHCl.sub.3                                 ______________________________________                                    

EXAMPLE 17 2-[4-(4-Phenoxybutoxy)phenyl]ethyl-1-tosylate ##STR30## Asuspension of 4.87 g (17 mmol) of 2-[4-(4-phenoxybutoxy)phenyl]ethanolin 15 ml of methylenechloride was stirred under nitrogen with 12 ml ofdry pyridine for 30 min and then cooled to -10° C. before 3.89 g (20.4mmol) of p-toluenesulfonyl chloride were added. The resulting mixturewas stirred for 2.5 hours at 0° C. and then mixed with water andextracted twice with ethyl acetate. The combined extracts were washedwith saturated aqueous sodium chloride and were then dried over sodiumsulfate and evaporated in vacuo. The solid residue was chromatographedon 73 g of silica gel using methylene chloride as eluent. The productcontaining fractions were combined and evaporated in vacuo. Aftertrituration with hexane, 6.28 g of the crystalline compound in theheading were obtained.

mp: 108° C.

Yield: 83.8% of theory

TLC-R_(f) : 0.55 (methylene chloride)

NMR (CDCl₃, 300 MHz): 2.0 [4] m, 2.45 [3] s, 2.9 [2] tr, J=8 Hz,3.95-4.1 [4] m, 4.2 [2] tr, J=8 Hz, 6.75 [2] d, J=8 Hz, 6.85-6.95 [3] m,7.0 [2] d, J=8 Hz, 7.25-7.35 [4] m, 7.7 [2] d, J=8 Hz.

EXAMPLES 18-21

Using the procedure of example 17 and the compounds of examples 10 to 13as starting material the following compounds were prepared:

    ______________________________________                                         ##STR31##                                                                    Nr.      n     m          Yield (%)                                                                             TLC-R.sub.f                                 ______________________________________                                        18       3     para 3     83.0    0.57                                                                          CH.sub.2 Cl.sub.2                           19       3     para 2     98.9    0.57                                                                          CH.sub.2 Cl.sub.2                           20       3     meta 2     92.7    0.55                                                                          CH.sub.2 Cl.sub.2                           21       3     ortho 2    89.1    0.62                                                                          CH.sub.2 Cl.sub.2                           ______________________________________                                    

EXAMPLES 22-25

Using the procedure of example 3 and the compounds of examples 7, 14, 15and 16 as starting materials the following compounds were prepared:

    ______________________________________                                         ##STR32##                                                                                            mp      yield                                         Nr.    n       X        [°C.]                                                                          [%]  TLC-R.sub.f *                            ______________________________________                                        22     4       O-para   49-50   88.0 0.32                                     23     4       O-meta   47-49   73.0 0.33                                     24     4       O-ortho  68-70   84.0 0.37                                     25     5       meta     --      78.0 0.32                                     ______________________________________                                         *The solvent was ethyl acetate:hexane (5:95)                             

EXAMPLE 26 2-[4-(4-Phenoxybutoxy)phenyl]ethyltriphenylphosphoniumtosylate ##STR33##

A solution of 4.85 g (11 mmol) of2-[4-(4-phenoxybutoxy)phenyl]ethyl-1-tosylate and 2.89 g (11 mmol) oftriphenylphosphine in 20 ml of acetonitrile was refluxed for 4 days. Thesolution was cooled and then the solvent was removed by evaporation invacuo to yield 7.7 g of compound in the heading in the form of a solidwhich was sufficiently pure to be used as obtained.

Yield: 99.6% of theory

NMR (CDCl₃, 300 MHz): 1.95 [4] broad s, 2.3 [3] s, 2.85-3.0 [2] m,3.65-3.8 [2] m, 3.95 [2] broad s, 4.0 [2] broad s, 6.7 [2] d, J=8 Hz,6.85-6.95 [3] m, 7.0 [2] d, J=8 Hz, 7.1 [2] d, J=8 Hz, 7.25 [2] tr, J=8Hz, 7.6-7.8 [17] m.

EXAMPLE 27 TO 35

The Wittig salts of the following table were prepared using theprocedure of example 26 and the compounds of examples 8 and 18 to 25.Examples 27 to 30 were prepared exactly according to the process ofexample 26 and example 31 to 35 were prepared in refluxing benzenerather than acetonitrile and were then crystallized from benzene beforeuse.

    ______________________________________                                         ##STR34##                                                                                                   Reflux        Yield                            Nr.  n      X        m    Y    time (h)                                                                             mp (°C.)                                                                      (%)                              ______________________________________                                        27   3      O para   3    Tos  65     --*    100**                            28   3      O para   2    Tos  72     --*    100**                            29   3      O meta   2    Tos  168    --*    100**                            30   3      O ortho  2    Tos  240    --*    100**                            31   4      O para   1    Br   24      55    65                               32   4      O meta   1    Br   24     127-128                                                                              100                              33   4      O ortho  1    Br   24     152    31                               34   5      -- meta  1    Br   75     151    100                              35   5      -- para  1    Br   15     201-202                                                                              88                               ______________________________________                                         *Many of these tosylates were solids, but were not recrystallized, so tha     a sharp melting point was not obtained.                                       **The residue was used without purification. If purification had been         carried out, the yield would probably have been somewhat less than 100%. 

EXAMPLE 27

NMR (CDCl₃, 300 MHz): 1.75-1.9 [4] m, 2.2 [2] quintet, J=8 Hz, 2.3 [3]s, 2.8 [2] tr, J=8 Hz, 3.4-3.55 [2] m, 4.05-4.2 [4] m, 6.8 [2] d, J=8Hz, 6.85-6.95 [3] m, 7.0-7.05 [4] m, 7.25 [2] tr, J=8 Hz, 7.55-7.85 [17]m.

EXAMPLE 28

NMR (CDCl₃, 300 MHz): 2.15-2.3 [2] m, 2.3 [3] s, 2.8-3.0 [2] m, 3.65-3.8[2] m, 4.0-4.2 [4] m, 6.7 [2] d, J=8 Hz, 6.85-6.95 [3] m, 7.05-7.15 [4]m, 7.3 [2] tr, J=8 Hz, 7.6-7.9 [17] m.

EXAMPLE 29

NMR (CDCl₃, 300 MHz): 2.15 [2] quintet, J=8 Hz, 2.3 [3] s, 2.9-3.05 [2]m, 3.7-3.85 [2] m, 4.1 [4] tr, J=8 Hz, 6.7 [2] d, J=8 Hz, 6.8 [1] s,6.85-6.95 [3] m, 7.0-7.1 [3] m, 7.25 [2] tr, J=8 Hz, 7.6-7.8 [17] m.

EXAMPLE 30

NMR (CDCl₃, 300 MHz): 2.15 [2] quintet, J=8 Hz, 2.3 [3] s, 2.9-3.0 [2]m, 3.55-3.7 [2] m, 3.95 [2] tr, J=8 Hz, 4.1 [2] tr, J=8 Hz, 6.75-6.85[4] m, 6.9 [1] tr, J=8 Hz, 7.0 [2] d, J=8 Hz, 7.1-7.25 [4] m, 7.55-7.8[17] m.

EXAMPLE 362-(4-Methoxycarbonylbenzyl)-2-(tert.butoxycarbonyl)-cyclohexanone##STR35##

2-Tert.butoxycarbonylcyclohexanone was prepared according to theprocedure of J. L. van der Barr and F. Bickelhaupt, Tetrahedron, 30,2447-2553, (1974). A solution of 49.5 g (0.25 mol) of this material in150 ml of dry dimethylformamide was stirred at 0° C. to 5° C. as a totalof 7.8 g (0.25 mol) of sodium hydride (80% suspension in oil) was addedin portions so that the evolution of gas did not become too vigorous.When the evolution of gas had ceased, a solution of 46.1 g (0.25 mol) ofmethyl 4-(chloromethyl)benzoate and 41.5 g (0.25 mol) of potassiumiodide in 100 ml of dry dimethylformamide was added dropwise as stirringat 0° C. was continued. The mixture was stirred for a further 30 minutesat 0° C. and then allowed to come to room temperature. It was thenpoured into ice water and extracted twice with ethyl acetate. Thecombined extract was washed with 10% sodium thiosulfate and then with asaturated aqueous sodium chloride solution. It was dried over sodiumsulfate and evaporated in vacuo. The 80 g of residue were heated inportions in a Kugelrohr still under a high vacuum to remove the volatilecomponents. The combined non-volatile residues were crystallized frompetroleum ether to yield 31.5 g of a white crystalline product.

mp: 60°-63° C.

Yield: 36% of theory

TLC-R_(f) : 0.36 (petroleum ether/ether 8:2)

NMR (CDCl₃, 300 MHz): 1.35 [9] s, 1.35-1.45 [1] m, 1.55-1.75 [3] m, 2.0[1] m, 2.35 [1] dq, J=14 Hz, 3 Hz, 2.5 [2] m, 2.9 [1] d, J=14 Hz, 3.3[1] d, J=14 Hz, 3.9 [3] s, 7.25 [2] d, J=8 Hz, 7.9 [2] d, J=8 Hz.

EXAMPLE 37 7-(4-Ethoxycarbonylphenyl)-6tert.butoxycarbonyl heptanic acidethyl ester ##STR36##

17.3 g (0.05 mol) of2-(4-methoxycarbonylbenzyl)-2tert.butoxycarbonyl-cyclohexanone areheated under reflux together with 5.6 g of potassium tert.butylate in100 ml absolute ethanol for 1 hour. After the mixture has cooled it isdiluted with water and extracted twice with ethyl acetate. The combinedethyl acetate phases are dried with sodium sulphate and concentrated byevaporation. 18 g of an oily product are thus obtained which issufficiently pure to be used for further reactions.

Yield: 88.6% of theory

Rf-value: 0.19 (petroleum: ether 8:2)

NMR (CDCl₃, 300 MHz): 1.25 [3] tr, J=8 Hz, 1.3 [9] s, 1.4 [3] tr, J=8Hz, 1.3-1.5 [3] m, 1.55-1.7 [3] m, 2.25 [2] tr, J=8 Hz, 2.55-2.65 [1] m,2.75 [1] dd, J=14 Hz, J=8 Hz, 2.95 [1] dd, J=14 Hz, J=10 Hz, 4.1 [2] q,J=8 Hz, 4.35 [2] q, J=8 Hz, 7.25 [2] J=8 Hz, 7.95 [2] d, J=8 Hz.

EXAMPLE 38 6-Tert.butoxycarbonyl-7-(4-methoxycarbonylphenyl)heptanoicacid methyl ester ##STR37##

49.5 g (0.25 mol) of 2-tert.butoxycarbonylcyclohexanone are dissolved in150 ml of absolute dimethylformamide under nitrogen and 9.0 g (0.3 mol)of an 80% sodium hydride suspension in spindle oil are added in portionsat 0° C. to 5° C. When the evolution of hydrogen has ended a solution of46.1 g (0.25 mol) of 4-chloromethylbenzoic acid methyl ester and 41.8 g(0.25 mol) of potassium iodide in 100 ml of absolute dimethylformamideare added dropwise at 0° C. The reaction mixture is subsequently stirredfor 30 minutes at 0° C. and is then heated to room temperature and 50 mlof methanol are added. Then the reaction mixture is poured into icewater and extracted with 600 ml of ethylacetate. The organic phase iswashed with a 10% thiosulphate solution and a saturated sodium chloridesolution and is dried with sodium sulphate and concentrated byevaporation. The residue is concentrated further in portions in aKugelrohr distillation apparatus under a high vacuum (air bathtemperature: 150° C.) and then chromatographed on 1.7 kg of silica gel(Merck 5:60, 0.04-0.064 mm) using petroleum ether/ether 8/207/3 as themobile solvent. A fraction is thus obtained which yields 35 g of a solidproduct after evaporation.

Yield: 37% of theory

R_(f) -value: 0.18 (petroleumether:ether 80:20)

NMR (CDCl₃, 300 MHz): 1.3 [9] s, 1.3-1.75 [6] m, 2.3 [2] tr, J=8 Hz,2.55-2.65 [1] m, 2.75 [1] dd, J=14 Hz, J=8 Hz, 2.95 [1] dd, J=14 Hz,J=10 Hz, 3.65 [3] s, 3.9 [3] s, 7.25 [2] d, J=8 Hz, 7.9 [2] d, J=8 Hz.

EXAMPLE 39 6-Carboxy-7-(4-ethoxycarbonylphenyl)heptanoic acid ethylester ##STR38##

18 g (44.3 mmol) of7-(4-ethoxycarbonylphenyl)-6-tert.-butoxycarbonylheptanoic acid esterare dissolved in 100 ml of trifluoroacetic acid and the solution isstirred vigorously for 1 hour. The trifluoroacetic acid is distilled offin vacuo and the residue is dissolved in ethyl acetate and washed with asaturated bicarbonate solution. The organic phase is dried withsodiumsulphate and concentrated by evaporation. 14.3 g of an oilyproduct are thus obtained, which is sufficiently pure to be used forfurther reaction.

Yield: 92% of theory

R_(f) -value: 0.48 (dichloromethane:methanol 95:5)

NMR (CDCl₃, 300 MHz): 1.25 [3] tr, J=8 Hz, 1.4 [3] tr, J=8 Hz, 1,3-1.75[6] m, 2.25 [2] tr, J=8 Hz, 2.7 [1] m, 2.8 [1] dd, J=14 Hz, J=8 Hz, 3.05[1] dd, J=14 Hz, J=10 Hz, 4.1 [2] q, J=8 Hz, 4.35 [2] q, J=8 Hz, 7.25[2] d, J=8 Hz, 7.95 [2] dd, J=8 Hz.

EXAMPLE 40 6-Carboxy-7-(4-methoxycarbonylphenyl)heptanoic acid methylester ##STR39##

35 g (95 mmols) of6-tert.butoxycarbonyl-7-(4-methoxycarbonylphenyl)heptanoic acid methylester are reacted following the same procedure as Example 39. In thismanner 26.7 g of a solid, m.p. 59°-60° C., are obtained which issufficiently pure to be used for further reactions.

Yield: 89.6% of theory

R_(f) -value: 0.45 (dichloromethane:methanol 95:5).

EXAMPLE 41 7-(4-Ethoxycarbonylphenyl)-6-hydroxymethylheptanoic acidethyl ester ##STR40##

14 g (40 mmol) of 6-carboxy-7-(4-ethoxycarbonylphenyl)heptanoic acidmethyl ester are dissolved under nitrogen in 60 ml of absolutetetrahydrofuran. 180 ml (50 mmol) of borane in tetrahydrofuran (contentdetermined by titration) are added dropwise at -10° C. When the dropwiseaddition has ended the mixture is stirred for 2 hours while cooling withice and is then diluted cautiously with a saturated bicarbonate solutionat 0° C. and extracted twice with ethyl acetate. The combined organicphases are dried with sodium sulphate and concentrated by evaporation.11.9 g of a yellow oily product are obtained, which is sufficiently pureto be used for further reactions.

Yield: 88.5% of theory

R_(f) -value: 0.58 (dichloromethane:methanol 95:5)

NMR (CDCl₃, 300 MHz): 1.25 [3] tr, J=8 Hz, 1.4 [3] tr, J=8 Hz, 1.3-1.85[7] m, ,3 [2] tr, J=8 Hz, 2.65 [1] dd, J=14 Hz, J=8 Hz, 2.75 [1] dd,J=14 Hz, J=8 Hz, 3.5 [2] d, J=6 Hz, 3.6 [1] tr, J=6 Hz, 4.1 [2] q, J=8Hz, 4.35 [2] q, J=8 Hz, 7.25 [2] d, J=8 Hz, 7.95 [2] d, J=8 Hz.

EXAMPLE 42 6-Hydroxymethyl-7-(4-methoxycarbonylphenyl)heptanoic acidmethyl ester ##STR41##

26.7 g (83 mmol) of 6-carboxy-7-(4-methoxycarbonylphenyl)heptanoic acidmethyl ester are reacted following the same procedure as in Example 41.22 g of an oily product are thus obtained which can be used without anyfurther purification.

Yield: 88% of theory

R_(f) -value: 0.55 (dichloromethane:methanol 95:5)

NMR (CDCl₃, 300 MHz): 1.3-1.85 [7] m, 2.3 [2] tr, J=8 Hz, 2.65 [1] dd,J=14 Hz, J=8 Hz, 2.75 [1] dd, J=14 Hz, J=10 Hz, 3.5 [2] d, J=8 Hz, 3.7[3] s, 3.9 [3] s, 7.25 [2] d, J=8 Hz, 7.9 [2] d, J=8 Hz.

EXAMPLE 43 7-(4-Ethoxycarbonylphenyl)-6-formyl-heptanoic acid ethylester ##STR42##

10 g (30 mmol) of 7-(4-ethoxycarbonylphenyl)-6-hydroxymethylheptanoicacid ethyl ester are dissolved in 100 ml of methylene chloride ofanalytical purity and methylene chloride containing 6.45 g (30 mmol) ofpyridinium chlorochromate is added under cooling with tapwater. Afterstirring for 2 hours at room temperature 3.25 g (15 mmol) of pyridiniumchlorochromate are once again added and the mixture is stirred for 1hour. The reaction mixture (including the oily residue) is applied to achromatographic column filled with 500 g of silica gel (Merck Si 60,0.04-0.063 mm) and elution is carried out under a slightly elevatedpressure using methylene chloride as the mobile solvent. A fraction isthus obtained which, after being evaporated in vacuo, yields 7.7 g of anoily product.

Yield: 77% of theory

R_(f) -value: 0.3 (petroleum ether:ether 60:40)

NMR (CDCl₃, 300 MHz): 1.25 [3] tr, J=8 Hz, 1.4 [3] tr, J=8 Hz, 1,4-1.75[6] m, 2.3 [2] tr, J=8 Hz, 2.6-2.7 [1] m, 2.75 [1] dd, J=14 Hz, J=8 Hz,3.05 [1] dd, J=14 Hz, J=8 Hz, 4.1 [2] q, J=8 Hz, 4.35 [2] q, J=8 Hz, 7.2[2] d, J=8 Hz, 7.95 [2] d, J=8 Hz, 9.65 [1] d, J=3 Hz.

EXAMPLE 44 6-Formyl-7-(4-methoxycarbonylphenyl)heptanoic acid methylester ##STR43##

20 g (64.9 mmol) of 6-hydroxymethyl-7-(4-methoxycarbonylphenyl)heptanoicacid methyl ester are oxidized and chromatographed following the sameprocedure as in Example 43. 8.4 g of an oily product are thus obtained.

Yield: 42.3% of theory

R_(f) -value: 0.12 (hexane:ether 70:30)

NMR (CDCl₃, 250 MHz): 1.35-1.8 [6] m, 2.3 [2] tr, J=8 Hz, 2.6-2.7 [1] m,2.75 [1] dd, J=14 Hz, J=8 Hz, 3.05 [1] dd, J=14 Hz, J=8 Hz, 3.65 [3] s,3.9 [3] s, 7.25 [d] 2, J=8 Hz, 7.95 [2] d, J=8 Hz, 9.65 [1] d, J=3 Hz.

EXAMPLE 456-(4-Ethoxycarbonylbenzyl)-7(E),9(E),11(Z),14(Z)-eicosatetraenoic acidethyl ester ##STR44##

0.19 g (0.6 mmol) of 2(E),4(Z),7(Z)-tridecatrienylphosphonic aciddiethyl ester (J. C. Buck, F. Ellis, P. North, Tetrahedron Letters,4161-4162, (1982)) are dissolved under nitrogen in 2 ml of absolutetetrahydrofuran. Then at -70° C. 0.31 ml (0.5 mmol) of n-butyllithium inhexane (content titrated) are added dropwise. After stirring for 30mins. at -70° C. 0.9 g of absolute 1,3-dimethyltetrahydropyrimidin-2-one(DMPU) are added dropwise, after which 0.17 g (0.5 mmol) of7-(4-ethoxycarbonylphenyl)-6-formylheptanoic acid ethyl ester in 1 ml ofabsolute tetrahydrofuran are added dropwise at -70° C. The reactionsolution is subsequently stirred at -70° C. for 15 minutes and is thenheated slowly to room temperature. It is then diluted with a saturatedsodium chloride solution and extracted with ethyl acetate. The organicphase is dried with sodium sulphate and concentrated by evaporation invacuo. The residue is subjected to flash chromatography on 10 g ofsilica gel (Merck Si 60, 0.04-0.063 mm) using hexane/ether 80/20 as themobile solvent. A fraction is thus obtained which after evaporationyields 0.13 g of an oily product.

Yield: 52% of theory

R_(f) -value: 0.4 (hexane:ether 80:20)

HPLC:Retention time: 13.07 minutes, Lichrosorb RP 18 7 μm) 25×4 mm,acetonitrile:water 80:20, 4.0 ml/min., 280 nm

NMR (CDCl₃, 200 MHz): 0.9 [3] tr, J=8 Hz, 1.25 [3] tr, J=8 Hz, 1.4 [3]tr, J=8 Hz, 1.2-1.45 [10] m, 1.5-1.65 [2] m, 2.0 [2] q, J=8 Hz, 2.25 [2]tr, J=8 Hz, 2.25-2.4 [1] m, 2.6-2.8 [2] m, 2.9 [2] tr, J=8 Hz, 4.1 [2]q, J=8 Hz, 4.35 [2] q, J=8 Hz, 5.26-5.46 [3] m, 5.46 [1] dd, J=14.8 Hz,J=8.9 Hz, 5.95 [1] dd, J=14.9 H, J=10.4 Hz, 5.98 [1] dd, J=10.8 Hz,J=10.8 Hz, 6.13 [1] dd, J=14.6 Hz, J=10.5 Hz, 6.36 [1] dd, J=14.5 Hz,J=11.2 Hz, 7.2 [2] d, J=8 Hz, 7.95 [d, J=8 Hz.

EXAMPLE 46 6-(4-Carboxybenzyl)-7-(E),9(E),11(Z),14(Z)-eicosatetraenoicacid ##STR45##

50 mg (0.1 mmol) of6-(4-ethoxycarbonylbenzyl)-7(E),9(E),11(Z),14(Z)-eicosatetraenoic acidethyl ester are dissolved in 1 ml of methanol and the solution is addedto a mixture of 10 ml of methanol and 1 ml of 45% sodium hydroxidesolution and the mixture is stirred at room temperature. Ether is thenadded in such a quantity that a clear solution is formed. The reactionsolution is left to stand for 4 hours at room temperature and is thendiluted with ice water and brought to pH=6 with a sodium citrate buffer(3.5 g of trisodium citrate-5,5-hydrate dissolved in 20 ml of 1 nhydrochloric acid). The cloudy aqueous solution is extracted twice withmethylene chloride and the combined organic phases are dried with sodiumsulphate and concentrated by evaporation. 32.6 mg of a solid residue arethus obtained as the product.

Yield: 88% of theory

R_(f) -value: 0.56 (dichloromethane:methanol 95:5)

HPLC:Retention time: 12.06 minutes, Lichrosorb RP-18 (7 μm) 25×4 mm,acetonitrile:water:glacial acetic acid 70:30:0.1, adjusted to pH=5.6with concentrated NH₃, 1.0 ml/min., 280 nm.

EXAMPLE 472-(4-Methoxycarbonylphenylthio)-2-tert.butoxycarbonylcyclohexanone##STR46##

A solution 10.8 g (53.2 mmol) of 4-methoxycarbonylphenylsulphenic acidchloride in 20 ml of methylene chloride (analytically pure) is addeddropwise to a solution of 11.4 g (57 mmol) of2-tert.butoxycarbonylcyclohexanone and 7.5 g (75 mmol) of triethylaminein 150 ml of methylene chloride. When the dropwise addition has endedthe mixture is subsequently stirred for 15 mins. and is then dilutedwith methylene chloride and the organic phase is washed with 2Nsulphuric acid and a saturated bicarbonate solution, dried with sodiumsulphate and concentrated by evaporation. 20.5 g of a crude product arethus obtained, which is chromatographed on 2 kg of silica gel (Merck Si60, 0.04-0.063 nm) using petroleum ether/ether 8:20 as the mobilesolvent. A fraction is thus obtained which, after being concentrated byevaporation, yields 11 g of a solid product.

Yield: 52.4% of theory

R_(f) -value: 0.24 (petroleum ether/ether 80:20)

NMR (CDCl₃, 300 MHz): 1.4 [9] s, 1.5-1.9 [4] m, 1.95-2.05 [1] m,2.4-2.55 [2] m, 2.65 [1] d tr, J=14 Hz, J=3 Hz, 3.9 [3] s, 7.55 [2] d,J=8 Hz, 7.95 [2] d, J=8 Hz.

EXAMPLE 48 6-(Methoxycarbonylphenylthio)-6-tert.butyloxycarbonylhexanoicacid methyl ester ##STR47##

1 g (30.2 mmol) of2-(4-methoxycarbonylphenylthio)-2-tert.butoxycarbonylcyclohexanone isdissolved, together with 0.37 g (3.3 mmol) of potassium tert.butylate,in 100 ml of methanol of reagent purity and the solutions is left tostand for 2 hours at room temperature. It is then diluted with 500 ml ofethyl acetate and the organic phase is washed with water and a saturatedsodium chloride solution, dried with sodium sulphate and concentrated byevaporation. After drying in a high vacuum 11.3 g of an oily product areobtained, which is sufficiently pure to be used for further reactions.

Yield: 94.2% of theory

R_(f) -value: 0.22 (petroleum ether:ether 80:20)

NMR (CDCl₃, 300 MHz): 1.3 [9] s, 1.3-1.55 [2] m, 1.6 [2] quintet, J=8Hz, 1.6-1.75 [1] m, 1.8-1.95 [1] m, 2.25 [2] tr, J=8 Hz, 3.6 [3] s, 3.65[1] dd, J=8 Hz, J=7 Hz, 3.85 [3] s, 7.5 [2] d, J=8 Hz, 7.85 [2] d, J=8Hz.

EXAMPLE 49 6-Carboxy-6-(4-methoxycarbonylphenylthio)hexanoic acid methylester ##STR48##

11.3 g (28.5 mmol) of6-(4-methoxycarbonylphenylthio)-6-tert.butoxycarbonyl-hexanoic acidmethylester are dissolved in 75 ml of trifluoroacetic acid and thesolution is stirred vigorously for 20 minutes at room temperature. Thetrifluoroacetic acid is then evaporated in vacuo, the residue isdissolved in ethyl acetate and washed 3 times with water. The organicphase is dried with sodium sulphate and concentrated by evaporation.After drying under a high vacuum 9.7 g of an oily product are obtained,which is sufficiently pure to be used for further reactions.

Yield: 10% of theory

R_(f) -value: 0.45 (dichloromethane:methanol 95:5)

NMR (CDCl₃, 300 MHz): 1.4-1.6 [2] m, 1.65 [2] quintet, J=8 Hz, 1.75-1.9[1] m, 1.9-2.05 [1] m, 2.35 [2] tr, J=8 Hz, 3.65 [3] s, 3.8 [1] tr, J=8Hz, 3.9 [3] s, 7.45 [2] d, J=8 Hz, 7.95 [2] d, J=8 Hz.

EXAMPLE 50 ##STR49## 7-Hydroxy-6-(4-methoxycarbonylphenylthio)-heptanoicacid methyl ester

200 ml (67 mmol) of borane in tetrahydrofuran (content determined) areadded dropwise under nitrogen at -10° C. to a solution of 9.6 g (28.2mmol) of 6-carboxy-6-(4-methoxycarbonylphenylthio)hexanoic acid methylester in 40 ml of absolute tetrahydrofuran. When the dropwise additionhas ended the mixture is stirred for 3 hours at 0° C. Then it is dilutedcatiously with saturated bicarbonate solution at 0° C., extracted twicewith ethyl acetate and the combined organic phases are dried with sodiumsulphate and concentrated by evaporation, 10.65 g of a crude product arethus obtained, which is chromatographed on 1 kg of silica gel (Merck Si60, 0.04-0.063 nm) using methylene chloride/methanol 99.5/0.5 to 98/2)as the mobile solvent. A fraction is thus obtained which yields 3.2 g ofan oily product after concentration by evaporation.

Yield: 34.8% of theory

R_(f) -value: 0.73 (methylene chloride/methanol 95:5)

NMR (CDCl₃, 300 MHz): 1.45-1.85 [6] m, 2.3 ([2] tr, J=8 Hz, 3.35 [1]quintet, J=8 Hz, 3.6-3.75 [2] m, 3.65 [3] s, 3.9 [3] s, 7.4 [2] d, J=8Hz, 7.95 [2] d, J=8 Hz.

EXAMPLE 51 6-Formyl-6-(4-methoxycarbonylphenylthio)hexanoic acid methylester ##STR50##

0.54 g (2.5 mmol) of pyridinium chlorochromate are added to a solutionof 0.65 g (2 mmol) of 7-hydroxy-6-(4-methoxycarbonylphenylthio)heptanoicacid methyl ester in 5 ml of methylene chloride. The reaction mixture isstirred for 1 hour at room temperature. Then the reaction mixture(including the black, oily residue) is poured onto a column filled with30 g of silica gel (Merck Si 60, 0.04-0.063 mm) and elution is carriedout using methylene chloride as the mobile solvent. A fraction is thusobtained which after evaporation yields 0.32 g of an oily product.

Yield: 50% of theory

R_(f) -value: 0.33 (methylene chloride:methanol 99:1)

NMR (CDCl₃, 200 MHz): 1.4-2.0 [6] m, 2.35 [2] tr, J=8 Hz, 3.6-3.7 [1] m,3.65 [3] s, 3.9 [3] s, 7.4 [2] d, J=8 Hz, 7.95 [2] d, J=8 Hz, 9.35 [1]d, J=7 Hz.

EXAMPLE 5210-Formyl-6-(4methoxycarbonylphenylthio)-7(E),9(E)-decadienoic acidmethyl ester ##STR51##

1.4 ml (2 mmol) of n-butyllithium in hexane (content titrated are addeddropwise to a solution of 1.16 g (3 mmol) of freshly distilled1-(tri-n-butylstannyl)-4-ethoxybutadiene (R. H. Wollenberg, TetrahedronLetters, 717-720 , (1978) in 16 ml of absolute tetrahydrofuran undernitrogen at -70° C. The temperature of the reaction solution is allowedto rise to -40° C. over a period of 15 minutes, the solution is thencooled again to -70° C. and a solution of 0.66 g (2 mmol) of6-formyl-6-(4-methoxycarbonylphenylthio)hexanoic acid methyl ester in 8ml of absolute tetrahydrofuran is added dropwise at this temperature.The mixture is stirred for 1 hour at -70° C., the cold reaction solutionis poured into a saturated bicarbonate solution and the mixture isextracted with ethyl acetate. The organic phase is dried with sodiumsulphate and concentrated by evaporation. The oily residue is dissolvedin 30 ml of a tetrahydrofuran/water 95:5 mixture and 0.2 g ofp-toluenesulphonic acid hydrate is added. After stirring the mixture for20 hours at room temperature 0.2 g of p-toluenesulphonic acid hydrateand 1 ml water are again added and the mixture is stirred for a further3 hours. Then a further 0.2 g of p-toluenesulphonic acid hydrate isadded and the mixture is stirred at room temperature for 4 hours. Themixture is worked up by diluting it with ethylacetate and extracting thediluted mixture twice with 2 n sodium hydroxide solution. The organicphase is dried with sodium sulphate and concentrated by evaporation. Theresidue is chromatographed with hexane/ether (80/20 to 60/40) on 80 g ofsilica gel (Merck Si 60, 0.04-0.063 nm). A fraction is thus obtainedwhich, after being concentrated by evaporation, yields 100 mg of an oilyproduct.

Yield: 13.3% of theory

R_(f) -value: 0.13 (hexane:ether 60:40)

Retention time: 10.4 minutes, Lichrosorb Si 50 (5 μm) 25×4 mm,n-hexane/ether 60/40, 280 nm.

NMR (CDCl₃, 200 MHz): 1,4-1,9 [6] m, 2,35 [2] tr, J=8 Hz, 3,65 [3] s,3,8 [1] q, J=8 Hz, 3,9 [3] s, 6,05 [1] dd, J=15 Hz, J=8 Hz, 6,0-6,25 [2]m, 7,0 [1] dd, J=15 Hz, J=10 Hz, 9,5 [1] d, J=8 Hz.

EXAMPLE 536-(4-Methoxycarbonylphenylthio)-7(E),9(E),11(Z),14(Z)-eicosatetraenoicacid methyl ester ##STR52##

0.3 ml (0.43 mmol) of n-butyllithium in hexane (content titrated) areadded dropwise to a solution of 0.36 g (0.65 mmol) of3(Z)-nonenyltriphenyl-phosphonium tosylate (I. Ernest, A. J. Main, R.Menasse, Tetrahedron Letters, 23, 167-170 (1982)) in 3 ml of abosolutetetrahydrofuran at -30° C. under nitrogen. The reaction solution issubsequently stirred for 10 minutes at -20° C. and is then cooled to-70° C. At -70° C. 0.38 ml of 1,3-dimethyltetrahydropyrimidin-2-one(DMPU) are first added dropwise, followed by a solution of 100 mg (0.266mmol) of 10-formyl-6-(4-methoxycarbonylphenylthio)-7(E),9(E)-decadienoicacid methylester in 1 ml of absolute tetrahydrofuran. The reactionsolution is heated slowly to room temperature, diluted with a saturatedbicarbonate solution and extracted with ethylacetate. The organic phaseis washed with a saturated sodium chloride solution, dried with sodiumsulphate and concentrated by evaporation. The residue is chromatographedwith hexane/ether 80/20 on 20 g of silica gel (Merck Si 60, 0.04-0.063mm). A fraction is thus obtained which, after evaporation, yields 63 mgof an oily product.

Yield: 48.9% of theory

R_(f) -value: 0.59 (hexane:ether 60:40)

HPLC: Retention time 14.2 minutes, Lichrosorb RP 18 (7 μm) 25×4 mm,acetonitrile/water 80/20, 2.0 ml/min., 280 nm.

NMR (CDCl₃, 300 MHz): 0.9 [3] tr, J=8 Hz, 1.2-1.4 [8] m, 1.45 [2] m,1.6-1.85 [4] m, 2.05 [2] q, J=8 Hz, 2.3 [2] tr, J=8 Hz, 2.9 [2] tr, J=8Hz, 3.65 [3] s, 3.8 [1] d tr, J=8 Hz, J=9 Hz, 3.9 [3] s, 5.25-5.5 [3] m,5.55 [1] d, J=14 Hz, J=9 Hz, 5.97 [1] 1] tr, J=11 Hz, 6.03-6.17 [2] m,6.41 [1] dd, J=13.8 Hz, J=10.9 Hz, 7.35 [2] d, J=8 Hz, 7.90 [2] d, J=8Hz.

EXAMPLE 546-(4-Carboxyphenylthio)-7(E),9(E),11(Z),14(Z)-eicosane-tetraenoic acid##STR53##

33 mg of6-(4-methoxycarbonylphenythio)-7(E),9(E),11(Z),14(Z)-eicosatetraenoicacid methylester are dissolved in 1 ml of methanol and the solution isadded to a mixture of 8 ml of methanol and 1 ml of 45% sodium hydroxidesolution. The clear solution is left to stand for 4 hours at roomtemperature, is then diluted with ice water and brought to a pH of 6with a citrate buffer (7 g of trisodium citrate-5,5-hydrate dissolved in20 ml of 1 n hydrochloric acid). The cloudy aqueous solution isextracted twice with methylene chloride and the combined organic phasesare dried with sodium sulphate and concentrated by evaporation. 25 mg ofa solid product are thus obtained.

Yield: 80% of theory

R_(f) -value: 0.1 (methylene chloride:methanol 95:5)

HPLC: Retention time 11.99 mins., Lichrosorb RP 18 (8 μm) 25×4 mm,acetonitrile/water/glacial acetic acid 70/30/0.1, adjusted to pH 5.6with concentrated NH₃, 1.0 ml/min, 280 nm.

EXAMPLE 55 3-(4-Methoxycarbonylphenyl)propanol ##STR54## 154.7 g (1.3mmol) of thionyl chloride are added dropwise to 1 l of methanol at -20°C. and 100 g (0.556 mol) of 3-(4-carboxyphenyl)propanol (J. Hora, Rec.Trav. Chim. Pays-Bas, 98, 45-49 (1976)) are then added at 0° C. Thereaction solution is stirred overnight at room temperature and is thenconcentrated by evaporation in vacuo, diluted with ethyl acetate andwashed twice with 2 n sodium hydroxide solution. The organic phase isdried with magnesium sulphate and concentrated by evaporation. 95.2 g ofan oily product are thus obtained, which is sufficiently pure for use infurther reactions.

Yield: 88.3% of theory

R_(f) -value: 0.12 (toluene:ethylacetate 9:1)

NMR (CDCl₃, 300 MHz): 1.9 [2] quintet, J=8 Hz, 2.3 [2] tr, J=8 Hz, 3.65[] tr, J=8 Hz, 3.9 [3] s, 7.25 [d, J=8 Hz, 7.95 [2] d, J=8 Hz.

EXAMPLE 56 3-(4-Methoxycarbonylphenyl)propanal ##STR55##

24.1 ml (0.34 mol) of absolute dimethylsulphoxide purity in 60 ml ofmethylene chloride of reagent purity are added dropwise to a solution of14.5 ml (0.17 mol) of oxalylchloride in 285 ml of methylene chloride.The reaction solution is subsequently stirred for 15 mins. at -60° C.and then a solution of 22 g (0.113 mol) of3-(4-methoxy-carbonylphenyl)-propanol in 60 ml of methylene chloride isadded dropwise at -60° C. The reaction solution is subsequently stirredfor 15 minutes at -60° C. and then 79 ml (0.56 mol) of triethylamine areadded dropwise at -60° C. The reaction mixture is allowed to reach roomtemperature, washed with water, dried with sodium sulphate andconcentrated by evaporation. The residue is chromatographed withtoluene/ethylacetate 9/1 on 800 g of silica gel (Merck Si 60, 0.04-0.063mm). A fraction is thus obtained which, after being concentrated byevaporation, yields 20.31 g of an oily product.

Yield: 93.5% of theory

R_(f) -value: 0.43 (toluene/ethylacetate 9:1)

NMR (CDCl₃, 250 MHz): 2.3 [2] tr, J=8 Hz, J=0.5 Hz, 3.0 [2] tr, J=8 Hz,3.9 [3] s, 7.3 [2] d, J=8 Hz, 8.0 [2] d, J=8 Hz, 9.8 [1] tr, J=0.5 Hz.

EXAMPLE 57 3-(4-Methoxycarbonylphenyl)-1-trimethylsilyloxy-1-propane##STR56## 9,61 g (50 mmol) 3-(4-Methoxycarbonylphenyl)propanal aredissolved, together with 8.3 ml (68 mmol) of trimethylchlorosilane and18.1 ml (0.13 mol) of triethylamine, in 15 ml of absolute dimethylformamide and the solution is heated under reflux for 2 hours undernitrogen. After cooling, the reaction mixture is diluted with asaturated bicarbonate solution and extracted with petroleum ether. Theorganic phase is washed 3 times with a saturated bicarbonate solution,dried with sodium sulphate and concentrated by evaporation. The residueis distilled under a high vacuum (distillation apparatus silylated).11.06 g of a pale yellow, oily product are thus obtained in the form ofa mixture of the cis- and trans-isomers.

Boiling point: 150° C. at 0.5 mm

Yield: 83.7% of theory

NMR (CDCl₃, 300 MHZ): 3.15 [0.84] d, J=8 Hz, trans-Isomer, 3.35 [1.16]d, J=8 Hz, cis-Isomer, 3.75 [3] s, 4.05 [0.58] q, J=8 Hz, cis-Isomer,5.0 [0.42] d tr, J=14 Hz, J=8 Hz, trans-Isomer, 6.2 [2] m, 7.1 [2] m,7.8 [2] m.

EXAMPLE 58 6-Formyl-7-(4-methoxycarbonylphenyl)-5-thiaheptanoic acidmethyl ester ##STR57##

A solution of 1.7 g (12.5 mmol) of freshly distilled sulphuryl chloridein 10 ml of methylene chloride is added dropwise to a solution of 3.33 g(12.5 mmol) of 4,4'-dithiobutyric acid dimethyl ester in 10 ml ofmethylene chloride under nitrogen at -70° C. The reaction solution isstirred for 20 minutes at 0° C., cooled again to -70° C. and a solutionof 6.61 g (25 mmol) of3-(4-methoxycarbonylphenyl)-1-trimethylsilyloxy-1-propene in 20 ml ofmethylene chloride is added dropwise. The reaction solution issubsequently stirred for 1 hour at -70° C. is then poured into 300 ml ofa saturated bicarbonate solution, shaken vigorously and extracted withethyl acetate. The organic phase is washed with a saturated sodiumchloride solution, dried with sodium sulphate and concentrated byevaporation. 8.2 g of an oily residue are thus obtained, which residueis chromatographed on 200 g of silica gel (Merck Si 60, 0.04-0.063 nm)with n-hexane/ether 60/40 as the mobile solvent. A fraction is thusobtained which, after being concentrated by evaporation, yields 3.3 g ofan oily product.

Yield: 40.6% of theory

R_(f) -value: 0.52 (toluene:ethyl acetate 80:20)

NMR (CDCl₃, 300 MHz): 1.8-1.95 [2] m, 2.35 [2] tr, J=8 Hz, 2.45 [2] tr,J=8 Hz, 2.95 [1] dd, J=14 Hz, J=6 Hz, 3.2 [1] dd, J=14 Hz, J=8 Hz, 3.45[1] ddd, J=8 Hz, J=6 Hz, J=3 Hz, 3.65 [3] s, 3.9 [3] s, 7.3 [2] d, J=8Hz, 8.0 [2] d, J=8 Hz, 9.3 [1] d, J=3 Hz.

EXAMPLE 5910-Formyl-6-(4-methoxycarbonylbenzyl)-5-thia-7(E),9(E)-decadienoic acidmethyl ester ##STR58##

1.1 ml (1.6 mmol) of n-butyllithium in hexane (content titrated) isadded dropwise to a solution of 0.94 g (2.4 mmol) of freshly distilled1-(tri-n-butylstannyl-4-ethoxybutadiene (R. H. Wollenberg, TetrahedronLetters, 717-720, (1978)) in 13 ml of absolute tetrahydrofuran at -70°C. under nitrogen. The temperature of the reaction solution is allowedto rise to -40° C. over a period of 15 minutes, the solution is cooledagain to -70° C. and a solution of 0.53 g of (1.6 mmol) of6-formyl-7-(4-methoxycarbonylphenyl)-5-thiaheptanoic acid methyl esteris added dropwise thereto. The reaction solution is subsequently stirredfor 1 hour at -70° C. and is then poured into a saturated bicarbonatesolution and extracted 3 times with ethylacetate. The combined organicphases are dried with sodium sulphate and concentrated by evaporation.The residue is dissolved in 30 ml of tetrahydrofuran 1.6 ml of water and0.2 g of p-toluene-sulphonic acid hydrate are added and the mixture isstirred at room temperature for 1.5 hours. It is then diluted withethylacetate, extracted twice with 2 n sodium hydroxide solution, andthe combined organic phases are dried with sodium sulphate andconcentrated by evaporation. The residue is chromatographed on 100 g ofsilica gel (Merck Si 60, 0.04-0.63 mm) usingn-hexane/ether/triethylamine 50/50/0.5 as the mobile solvent. A fractionis thus obtained which, after being concentrated by evaporation, yields0.11 g of the product.

Yield: 18.1% of theory

R_(f) -value: 0.24 (n-hexane/ether 1:1)

NMR (CDCl₃, 300 MHz): 1.75-1.95 [2] m, 2.3-2.55 [4] m, 2.9-3.1 [2] m,3.55 [1] q, J=8 Hz, 3.65 [3] s, 3.9 [3] s, 6.02 [1] dd, J=14 Hz, J=8 Hz,6.08 [1] dd, J=14 Hz, J=8 Hz, 6.16 [1] dd, J=14 Hz, J=10 Hz, 7.05 [1]dd, J=14 Hz, J=8 Hz, 7.25 [2] d, J=8 Hz, 7.95 [2] d, J=8 Hz, 9.55 [1] d,J=8 Hz.

EXAMPLE 606-(4-Methoxycarbonylbenzyl)-5-thia-7(E),9(E),11(Z)14(Z)-eicosatetraenoicacid methyl ester ##STR59##

0.17 ml (0.266 mmol) of n-butyllithium in hexane (content titrated) areadded dropwise to a solution of 0.18 g (0.32 mmol) of 3(Z)-nonenyltriphenylphosphonium tosylate (I. Ernest, A. J. Main, P.Menasse, Tetrahedron Letters, 23, 167-170 (1982) in 3 ml of absolutetetrahydrofuran at -30° C. The reaction solution is subsequently stirredfor 10 minutes at -30° C., is then cooled to -70° C. and 0.5 ml ofabsolute 1,3-dimethyltetrahydropyrimidin-2-one (DMPU) is added dropwiseat this temperature. Then a solution of 0.1 g (0.266 mmol) of10-formyl-6-(4-methoxycarbonylbenzyl)-5-thia-7(E),9(E)-decadienoic acidmethyl ester in 0.6 ml of absolute tetrahydrofuran is added dropwise at-70° C. After stirring the mixture for 1 hour at -70° C. 0.2 ml ofmethanol is added, the reaction solution is allowed to warm to roomtemperature, slowly diluted with water and extracted with ethylacetate.The organic phase is washed with water and a saturated sodium chloridesolution, dried with sodium sulphate and concentrated by evaporation.The residue is chromatographed on 22 g of silica gel (Merck Si 60,0.04-0.063 mm) using n-hexane/ether 80/20 as the mobile solvent. Afraction is thus obtained which, after being concentrated byevaporation, yields 7.4 mg of the product.

Yield: 5.7% of theory

R_(f) -value: 0.29 (hexane:ether 70:30)

NMR (CDCl₃, 300 MHz): 0.9 [3] tr, J=8 Hz, 1.2-1.4 [6] m, 1.8-1.95 [2] m,2.05 [2] q, J=8 Hz, 2.3-2.55 [4] m, 2.85-3.05 [4] m, 3.5 [1] d, tr, J=9Hz, J=8 Hz, 3.65 [3] s, 3.9 [3] s, 5.27-5.45 [3] m, 5.48 [1] dd, J=14.7Hz, J=9.4 Hz, 5.94-6.04 [2] m, 6.15 [1] dd, J=14.6 Hz, J=10.7 Hz, 6.43[1] dd, J=14.5 Hz, J=11.2 Hz, 7.25 [2] d, J=8 Hz, 7.95 [2] d, J=8 Hz.

EXAMPLE 61 6-(Carboxybenzyl)-5-thia-7(E),9(E),11(Z),14(Z)-eicosatetraenoic acid ##STR60##

7.4 mg of 6-(4-methoxycarbonylbenzyl)-5-thia-7(E),9(E),11(Z),14(Z)-eicosatetraenoic acid methyl ester are saponified following the sameprocedure as in Example 54. 5.6 mg of the product are thus obtained.

Yield: 81.8% of theory

R_(f) -value: 0.6 (methylene chloride:methanol 9:1)

HPLC: Retention time 10.5 minutes, Lichrosorb RP 18 (7 μm), 25×4 mm,acetonitrile/water/glacial acetic acid 70/30/0.1, adjusted to pH 5.6with concentrated NH₃, 1.0 ml/min., 280 nm.

EXAMPLE 62 6-Carboxy-6-(4-methoxycarbonylphenyl)hexanoic acid methylester ##STR61## 15,4 ml (0, 11 mol) diisopropylamine are dissolved in200 ml of absolute tetrahydrofuran under nitrogen and 71.5 ml (0.11 mol)of n-butyllithium in hexane (content titrated) are added dropwise at 0°C. Then a solution of 9.29 g of 4-methoxycarbonylphenylacetic acid in 20ml of absolute tetrahydrofuran is added dropwise at 0° C., then 15 ml ofabsolute 1,3-dimethyltetrahydropyrimidin-2-one (DMPU) are added dropwiseat 0° C. and the reaction solution is stirred for 1 hour at thistemperature. Then a solution of 13.37 g (67.9 mmol) of1-(4-bromobutyl)-4-ethyl-2,6,7-trioxabicyclo[2.2.2]octane (preparedanalogously as described by E. J. Corey, N. Raju, Tetrahedron Letters,24, 5571-5574 (1983)) in 10 ml of absolute1,3-dimethyl-tetrahydropyrimidine (DMPU) is added dropwise at 0° C. andthe reaction solution is subsequently stirred at 0° C. for 1.5 hours. Itis then diluted with 2 n sulphuric acid and extracted 3 times with ethylacetate. The combined organic phases are dried with sodium sulphate andconcentrated by evaporation, the residue is dissolved in 200 ml ofmethanol and 11.8 ml (95.8 mmol) of 1,5-diazabicyclo (4,3,0)non-5-ene(DBN) are added. The mixture is left to stand at room temperature for 18hours, the methanol is then substantially evaporated in vacuo and theresidue is dissolved in ethyl acetate. The ethyl acetate solution iswashed once with 2 n sulphuric acid and 3 times with a saturated sodiumchloride solution, dried with sodium sulphate and concentrated byevaporation. The residue is chromatographed with methylenechloride/methanol 95/5 and kg of silica gel (Merck Si 60, 0.04-0.63 mm).A fraction is thus obtained which after being concentrated byevaporation, yields 6.8 g of an oily product.

Yield: 46% of theory

R_(f) value: 0.63 (methylene chloride:methanol 9:1)

NMR (CDCl₃, 300 MHz): 1.2-1.4 [2] m, 1.55-1.7 [2] quintet, J=8 Hz,1.7-1.85 [1] m, 2.0-2.15 [1] m, 2.3 [2] tr, J=8 Hz, 3.6 [1] tr, J=8 Hz,3.65 [3] s, 3.9 [3] s, 7.4 [2] d, J=8 Hz, 8.0 [2] d, J=8 Hz.

EXAMPLE 63 7-Hydroxy-6-(methoxycarbonylphenyl)heptanoic acid methylester ##STR62##

73.5 ml (22 mmol) of borane in tetrahydrofuran (content determined) areadded dropwise at -10° C., under nitrogen to a solution of 6.8 g (22mmol) of 6-carboxy-6-(4-methoxycarbonylphenyl)hexanoic acid methyl esterin 100 ml of absolute tetrahydrofuran. The reaction solution is allowedto warm to room temperature and is subsequently stirred for 2 hours. Itis worked up by cooling it to 0° C. and diluting it cautiously withwater. It is extracted twice with ethyl acetate and the combined organicphases are washed with a saturated bicarbonate solution and a saturatedsodium chloride solution, dried with sodium sulphate and concentrated byevaporation. The residue is chromatographed with methylenechloride/methanol 99/1 to 95/5 on 600 g of silica gel (Merck Si 60,0.04-0.063 mm). A fraction is thus obtained which after beingconcentrated by evaporation, yields 3.51 g of an oily product.

Yield: 54.1% of theory

R_(f) -value: 0.65 (methylene chloride:methanol 95:5)

NMR (CDCl₃, 300 MHz): 1.15-1.3 [2] m, 1.5-1.7 [3] m, 1.7-1.85 [1] m,2.25 [2] tr, J=8 Hz, 2.85 [1] quintet, J=8 Hz, 3.65 [3] s, 3.75 [2] d,J=8 Hz, 3.9 [3] s, 7.3 [2] d, J=8 Hz, 8.0 [2] d, J=8 Hz.

EXAMPLE 64 6-Formyl-6-(4-methoxycarbonylphenyl)hexanoic acid methylester ##STR63##

3.59 g (16.6 mmol) of pyridinium chlorochromate are added to a solutionof 3.5 g (11.9 mmol) of 7-hydroxy-6-(methoxycarbonylphenyl)heptanoicacid methyl ester in 35 ml of methylene chloride of reagent purity. Thereaction mixture is stirred for 1.5 hours at room temperature and thenchromatographed with methylene chloride on 100 g of silica gel (silicagel Si 60, 0.04-0.063 mm). A fraction is thus obtained which, afterbeing concentrated by evaporation, yields 2.64 g of an oily crudeproduct. On chromatographing the crude product a second time on 150 g ofsilica gel (Merck Si 60, 0.04-0.063 mm) using n-hexane/ether 70/30 asthe mobile solvent a fraction is obtained which, after beingconcentrated by evaporation, yields 1.42 g of a clean, oily product.

Yield: 40.9% of theory

R_(f) -value: 0,16 (n-hexane:ether 60:40)

NMR (CDCl₃, 300 MHz): 1.2-1.4 [2] m, 1.55-1.85 [3] m, 2.05-2.2 [1] m,2.3 [2] tr, J=8 Hz, 3.6 [1] tr d, J=8 Hz, J=0.5 Hz, 3.65 [3] s, 3.9 [3]s, 7.3 [2] d, J=8 Hz, 8.05 [2] d, J=8 Hz, 9.7 [1] d, J=0.5 Hz.

EXAMPLE 656-(4-Methoxycarbonylphenyl)-7(E),9(E),11(Z),14(Z)-eicosatetraenoic acidmethyl ester ##STR64##

0.19 g (0.6 mmol) of 2(E),4(Z),7(Z)-tridecatrienylphosphonic aciddiethyl ester (S. C. Buck, F. Ellis, P. North, Tetrahedron Letters,4161-4162, (1982)) are dissolved in 2 ml of absolute tetrahydrofuranunder nitrogen. Then 0.325 ml (0.5 mmol) of n-butyllithium in hexane(content titrated) are added dropwise at -70° C. After stirring for 30minutes at -70° C., 0.9 ml of absolute1,3-dimethyltetrahydropyrimidin-2-one (DMPU) are added dropwise, then0.25 g (0.856 mmol) of 6-formyl-6-(4-methoxycarbonylphenyl)hexanoic acidmethyl ester dissolved in 1 ml of absolute tetrahydrofuran are addeddropwise at -70° C. The reaction mixture is allowed to reach roomtemperature very slowly, is diluted with a saturated bicarbonatesolution and is extracted twice with ethyl acetate. The combined organicphases are washed with a saturated sodium chloride solution andconcentrated by evaporation. The residue is chromatographed withn-hexane/ether 90/10 on 10 g of silica gel (Merck Si 60, 0.04-0.063 mm).A fraction is thus obtained which, after being concentrated byevaporation, yields 19 mg of an oily product. A second, more polarfraction yields, after being concentrated by evaporation, 80 mg of thealdehyde starting material.

Yield: 5% of theory

R_(f) -value: 0.61 (n-hexane:ether 60:40)

HPLC: Retention time 7.53 minutes. Lichrosorb RP 18 (7 μm) 25×4 mm,acetonitrile: water 80:20, 4.0 ml/min., 280 nm.

NMR (CDCl₃, 300 MHz): 0.9 [3] tr, J=8 Hz, 1.2-1.4 [8] m, 1.65 [2]quintet, J=8 Hz, 1.75 [2] q, J=8 Hz, 2.05 [2] q, J=8 Hz, 2.3 [2] tr, J=8Hz, 2.95 [2] tr, J=8 Hz, 3.35 [1] q, J=8 Hz, 3.65 [3] s, 3.9 [3] s,5.28-5.47 [3] m, 5.79 [1] dd, J=14.3 Hz, J=7.8 Hz, 6.0 [1] tr, J=11 Hz,6.05-6.23 [2] m, 6.44 [1] dd, J=13.5 Hz, J=11.5 Hz, 7.25 [2] d, J=8 Hz,8.0 [2] d, J=8 Hz.

EXAMPLE 66 6-(4-Carboxyphenyl)-7(E),9(E),11(Z),14(Z)-eicosatetraenoicacid ##STR65##

A solution of 19 mg of6-(4-methoxycarbonylphenyl)-7(E),9(E),11(Z),14(Z)-eicosatetraenoic acidmethyl ester in 1 ml of methanol is added to a solution of 0.2 ml of 45%sodium hydroxide solution in 2 ml of methanol. Such a quantity of ether(about 1 ml) is added dropwise with stirring until a clear solution isformed. This solution is left to stand for 3.5 hours at room temperatureis then diluted with ice water and is brought to a pH of 3 with 2 nsulphuric acid. The cloudy aqueous phase is extracted with ethyl acetateand the ethyl acetate phase is washed with water, dried with sodiumsulphate and concentrated by evaporation, 16 mg of a solid residue arethus obtained as the product.

Yield: 89.8% of theory

R_(f) -value: 0.18 (methylene chloride:methanol 95:5)

HPLC: Retention time 12.63 minutes, Lichrosorb RP 18 (7 μm) 25×4 mm,acetonitrile:water:glacial acetic acid 70:30:1, adjusted to a pH of 5.6with concentrated NH₃, 1.0 ml/min., 280 nm.

EXAMPLE 676-(4-Methoxycarbonylbenzyl)-9-[3-(3-phenoxypropoxy)phenyl]-7(Z)-nonenoicacid methyl ester ##STR66##

0.79 ml (1 mmol) of n-butyllithium in hexane (content titrated) areadded dropwise under nitrogen at -28° C. to a solution of 0.826 g (1.2mmol) of 2-[3-(3-phenoxypropoxy)phenyl]ethyltriphenylphosphoniumtosylate in 11 ml of absolute tetrahydrofuran. The mixture issubsequently stirred at -25° C. for 15 minutes, then cooled to -70° C.and 1.8 ml of absolute 1,3-dimethyltetrahydropyrimidin-2-one are addedat -70° C. Then a solution of 0.31 g (1 mmol) of6-formyl-7-(4-methoxycarbonylphenyl)heptanoic acid methyl ester in 2 mlof absolute tetrahydrofuran is added dropwise at -70° C. After stirringfor 30 mins. at -70° C. 0.5 ml of methanol is added dropwise and thereaction mixture is allwed to warm slowly to 0° C. It is then stirredfor 1 hour at 0° C., diluted with ethyl acetate and washed with waterand a saturated sodium chloride solution. The organic phase is driedwith sodium sulphate and concentrated by evaporation. The residue ischromatographed with n-hexane/ether 75/25 on 50 g of silica gel (MerckSi 60, 0.04-0.063 mm). A fraction is thus obtained which, afterevaporation yields 0.27 g of the product in the form of a pale yellowoil.

Yield: 49.6% of theory

R_(f) -value: 0.36 (n-hexane:ether 70:30)

NMR (CDCl₃, 300 MHz): 1.3-1.7 [6] m, 2.2-2.3 [4] m, 2.55 [1] dd, H=13Hz, J=8 Hz, 2.65-2.8 [2] m, 3.0 [1] dd, J=14 Hz, J=8 Hz, 3.15 [1] dd,J=14 Hz, J=8 Hz, 3.65 [3] s, 3.9 [3] s, 4.1 [2] tr, J=8 Hz, 4.15 [2] tr,J=8 Hz, 5.2 [1] tr, J=10 Hz, 5.5 [1] d, tr, J=10 Hz, J=7 Hz, 6.45 [1] d,J=8 Hz, 6.55 [1] s, 6.7 [1] dd, J=8 Hz, J=1 Hz, 6.85-6.95 [3] m, 7.05[1] tr, J=8 Hz, 7.2 [2] d, J=8 Hz, 7.25-7.3 [2] m, 7.9 [2] d, J=8 Hz.

EXAMPLE 686-(4-Carboxybenzyl)-9-[3-(3-phenoxypropoxy)phenyl]-7(Z)-nonenoic acid##STR67##

3.2 ml of 45% sodium hydroxide solution are added at 0° C. to a solutionof 0.24 g (0.44 mmol) of the product of Example 67 in 19 ml of methanol.After heating the reaction solution to room temperature such a quantityof methylene chloride (about 3 ml) is added with stirring until a clearsolution is formed. The reaction solution is left to stand for 6 hoursat room temperature and is then diluted with water, brought to a pH of 3with 2 n sulphuric acid and extracted twice with ethyl acetate. Thecombined organic phases are dried with sodium sulphate and concentratedby evaporation.

Yield: 92.2% of theory

NMR (CDCl₃, 300 MHz): 1.3-1.7 [6] m, 2.25 [2] quintet, J=8 Hz, 2.3 [2]tr, J=8 Hz, 2.55 [1] d, J=13 Hz, J=8 Hz, 2.65-2.8 [2] m, 3.0 [1] dd,J=14 Hz, J=8 Hz, 3.15 [1] dd, J=14 Hz, J=8 Hz, 4.1 [2] tr, J=8 Hz, 4.15[2] tr, J=8 Hz, 5.2 [1] tr, J=10 Hz, 5.55 [1] d, tr, J=10 Hz, J=7 Hz,6.5 [1] d, J=8 Hz, 6.55 [1] s, 6.7 [1] dd, J=8 Hz, J=1 Hz, 7.85-7.95 [3]m, 7.1 [ 1] tr, J=8 Hz, 7.2-7.3 [4] m, 7.95 [2] d, J=8 Hz.

EXAMPLE 696-(4-Methoxycarbonylbenzyl)-10-[4-(3-phenoxypropoxy)phenyl]-7(Z)-decenoicacid methyl ester ##STR68##

0.84 g (1.2 mmol) of3-[4-(4-phenoxy-butoxy)phenyl]propyltriphenylphosphonium tosylate arereacted with 0.31 g (1 mmol) of6-formyl-7-(4-methoxycarbonylphenyl)heptanoic acid methyl esterfollowing the same procedure as in Example 67. 0.12 g of a solid productare thus obtained.

Yield: 18% of theory

NMR (CDCl₃, 300 MHz): 1.15-1.7 [6] m, 1.9-2.15 [2] m, 2.2-2.6 [8] m, 2.7[1] dd, J=14 Hz, J=7 Hz, 3.65 [3] s, 3.9 [3] s, 4.1-4.2 [4] m, 5.05 [1]tr, J=10 Hz, 5.35 [1] d, tr, J=14 Hz, J=10 Hz, 6.8 [2] d, J=8 Hz,6,9-7.0 [5] m, 7.2 [2] d, J=8 Hz, 7.25-7.3 [2] m, 7.95 [2] d, J=8 Hz.

EXAMPLE 706-(4-Carboxybenzyl)-10-[4-(4-phenoxypropoxy)pheny]-7(Z)-decanoic acid##STR69##

0.11 g of the product described in Example 69 are saponified followingthe same procedure as in Example 68. 0.1 g of a solid product areobtained.

Yield: 95.7% of theory

NMR (CDCl₃, 300 MHz): 1.1-1.7 [6] m, 1.9-2.15 [2] m, 2.15-2.6 [8] m,2.65 [1] dd, J=14 Hz, J=7 Hz, 4.05-4.15 [4] m, 5.05 [1] tr, J=10 Hz,5.35 [1] d, tr, J=14 Hz, J=10 Hz, 6.8 [2] d, J=8 Hz, 6.85-7.0 [5] m, 7.2[2] d, J=8 Hz, 7.2-7.3 [2] m, 8.0 [2] d, J=8 Hz.

EXAMPLE 716-(4-Methoxycarbonylbenzyl)-9-[4-(4-phenoxybutoxy)-phenyl]-7(Z)-nonenoicacid methyl ester ##STR70##

0.843 g (1.2 mmol) of2-[4-(4-phenoxybutoxy)-phenyl]ethyltriphenylphosphonium tosylate arereacted with 0.31 g (1 mmol) of6-formyl-7-(4-methoxycarbonylphenyl)heptanoic acid methyl esterfollowing the same procedure as in Example 67. 0.32 g of the product arethus obtained.

Yield: 57.3% of theory

R_(f) -value: 0.17 (n-hexane:ether 8:2)

NMR (CDCl₃, 300 MHz): 1.3-1.7 [6] m, 1.9-2.0 [4] m, 2.3 [2] tr, J=8 Hz,2.55 [1] dd, J=13 Hz, J=8 Hz, 2.65-2.8 [2] m, 2.95-3.15 [2] m, 3.65 [2]s, 3.9 [3] s, 3.95-4.05 [4] m, 5.2 [1] tr, J=10 Hz, 5.45 [1] d tr, J=10Hz, J=7 Hz, 6.7-6.8 [3] m, 6.9-7.0 [3] m, 7.2-7.35 [5] m, 7.95 [2] d,J=8 Hz.

EXAMPLE 726-(4-Carboxybenzyl)-9-[4-(4-phenoxybutoxy)phenyl]-7(Z)-nonenoic acid##STR71##

0.27 g of the product described in Example 70 are saponified followingthe same procedure as in Example 68. 0.24 g of a solid product isobtained.

Yield: 93.6% of theory

R_(f) -value: 0.2 (methylene chloride:methanol 95:5)

NMR (CDCl₃, 300 MHz): 1.3-1.7 [6] m, 1.9-2.0 [4] m, 2.25 [2] tr, J=8 Hz,2.55 [1] dd, J=13 Hz, J=8 Hz, 2.65-2,8 [2] m, 2.95-3.15 [2] m, 3.95-4.05[4] m, 5.2 [1] tr, J=10 Hz, 5.45 [1] d tr, J=10 Hz, J=7 Hz, 6.7-6.8 [9]m, 6.85-6.95 [3] m, 7.15-7.3 [5] m, 7.95 [2] d, J=8 Hz.

EXAMPLE 736-(4-Methoxycarbonylbenzyl)-9-[4-(4-phenoxybutoxy)phenyl]-5-thia-7(Z)-nonenoicacid methyl ester ##STR72##

0.843 g (1.2 mmol) of2-[4-(4-phenoxybutoxy)-phenyl]ethyltriphenylphosphonium tosylate arereacted with 0.32 g (1 mmol) of6-formyl-7-(4-methoxycarbonylphenyl)-5-thiaheptanoic acid methylesterfollowing the same procedure as in Example 67. 0.22 g of the product arethus obtained.

Yield: 38% of the theory

R_(f) -value: 0,44 (n-hexane:ether 60:40)

NMR (CDCl₃, 300 MHz): 1.8-2.0 [6] m, 2.4 [2] tr, J=8 Hz, 2.45-2.6 [2] m,2.8 [1] dd, J=14 Hz, J=8 Hz, 3.0-3.1 [3] m, 3.65 [3] s, 3.9 [3]s,3.9-4.05 [5] m, 5.2 [1] tr, J=10 Hz, 5.55 [1] d tr, J=10 Hz, J=7 Hz, 6.7[3] s, 6.85-6.95 [3] m, 7.2-7.3 [5] m, 7.95 [2] d, J=8 Hz.

EXAMPLE 746-(4-Carboxybenzyl)-9-[4-(4-phenoxybutoxy)phenyl]-5-thia-7(Z)-nonenoicacid ##STR73##

0.1 g of the product obtained in Example 72 is saponified following thesame procedure as in Example 68. 90 mg of a solid product are thusobtained.

Yield: 96% of theory

R_(f) -value: 0.5 (methylene chloride:methanol 9:1)

NMR (CDCl₃, 300 MHz): 1.8-2.0 [6] m, 2.35-2.65 [4] m, 2.8 [1] d, J=13Hz, J=8 Hz, 3.0-3.15 [3] m, 3.9-4.05 [5] m, 5.35 [1] tr, J=10 Hz, 5.6[1] d tr, J=10 Hz, J=8 Hz, 6.7 [3] s, 6.85-6.95 [3], 7.2-7.3 [5] m, J=8Hz.

EXAMPLE 756-(4-Methoxycarbonylbenzyl)-10-[4-(3-phenoxypropoxy)phenyl]-5-thia-7(Z)-decenoicacid methyl ester ##STR74##

0.84 g (1.2 mmol) of3-[4-(3-phenoxypropoxy)phenyl]propyltriphenylphosphonium tosylate arereacted with 0.32 g (1 mmol) of6-formyl-7-(4-methoxycarbonylphenyl)-5-thiaheptanoic acid methyl esterfollowing the same procedure as in Example 67. 0.21 g of the product arethus obtained.

Yield: 36.4% of theory

R_(f) -value: 0.43 (hexane:ether 60:40)

NMR (CDCl₃, 300 MHz): 1.75-1.9 [2] m, 1.9-2.5 [10] m, 2.7 [1] dd, J=14Hz, J=10 Hz, 2.95 [1] dd, J=14 Hz, J=7 Hz, 3.65 [3] s, 3.8 [1] tr d,J=10 Hz, J=7 Hz, 3.9 [3] s, 4.1-4.2 [4] m, 5,2 [1] tr, J=10 Hz, 5.45 [1]d tr, J=10 Hz, J=8 Hz, 6.8 [2] d, J=8 Hz, 6.85-7.0 [5] m, 7.15-7.3 [4]m, 7.95 [2] d, J=8 Hz.

EXAMPLE 766-(4-Carboxybenzyl)-10-[4-(3-phenoxypropoxy)phenyl]-5-thia-7(Z)-decenoicacid ##STR75##

0.17 g of the product obtained in Example 74 are saponified followingthe same procedure as in Example 68. 0.15 g of the product are thusobtained.

Yield: 92.7% of theory

R_(f) -value: 0.3 (methylene chloride:methanol 95:5).

EXAMPLE 776-(4-Methoxycarbonylbenzyl)-9-[3-(3-phenoxypropoxy)phenyl]-5-thia-7(Z)-nonenoicacid methyl ester ##STR76##

0.84 g (1.2 mmol) of2-[3-(3-phenoxypropoxyphenyl]ethyltriphenylphosphonium tosylate arereacted with 0.32 g (1 mmol) of6-formyl-7-(4-methoxycarbonylphenyl)-5-thiaheptanoic acid methyl esterfollowing the same procedure as in example 67. 0.17 g of the product arethus obtained.

Yield: 30.2% of theory

R_(f) -value: 0.18 (n-hexane:ether 7:3)

NMR (CDCl₃, 300 MHz): 1.9 [2] quintet, J=8 Hz, 2.25 [2] quintet, J=8 Hz,2.35 [2] tr, J=8 Hz, 2.4-2.6 [2] m, 2.8 [1] dd, J=14 Hz, J=10 Hz, 3.05[1] dd, J=14 Hz, J=8 Hz, 3.1-3.2 [2] m, 3.65 [3] s, 3.9 [3] s, 3.9-4.0[1] m, 4.1 [2] tr, J=8 Hz, 4.15 [2] tr, J=8 Hz, 5.35 [1] tr, J=10 Hz,5.6 [1] d, tr, J=10 Hz, J=8 Hz, 6.4 [1] d, J=8 Hz, 6.55 [1] s, 6.7 [1]dd, J=8 Hz, J=1 Hz, 6.9-7.0 [3] m, 7.05 [1] tr, J=8 Hz, 7.25-7.35 [4] m,7.95 [2] d, J=8 Hz.

EXAMPLE 786-(4-Carboxybenzyl)-9-[3-(3-phenoxypropoxy)phenyl]-5-thia-7(Z)-nonenoicacid ##STR77##

0.15 g of the product described in Example 76 are saponified followingthe same procedure as in Example 68. 0.13 g of the solid product arethus obtained.

Yield: 80.5% of theory

R_(f) -value: 0.3 (methylenechloride:methanol 95:5)

NMR (CDCl₃, 300 MHz): 1.8-1.95 [2] m, 2.25 [2] quintet, J=8 Hz,2.35-2.65 [4] m, 2.8 [1] dd, J=14 Hz, J=10 Hz, 3.05 [1] dd, J=14 Hz, J=8Hz, 3.05-3.2 [2] m, 3.95 [1] tr, d, J=10 Hz, J=8 Hz, 4.05-4.2 [4] m,5.4.[1] tr, J=10 Hz, 5.65 [1] d tr, J=10 Hz, J=8 Hz, 6.4 [1] d, J=8 Hz,6.5 [1] s, 6.7 [1] dd, J=8 Hz, J=1 Hz, 6.85-6.95 [3] m, 7.1 [1] tr, J=8Hz, 7.2-7.3 [4] m, 8.0 [2] d, J=8 Hz.

EXAMPLE 796-(4-Methoxycarbonylbenzyl)-9-[2-(3-phenoxypropoxy)phenyl]-5-thia-7(Z)-nonenoicacid methyl ester ##STR78##

0.84 g (1.2 mmol) of2-[2-(3-phenoxypropoxy)phenyl]ethyltriphenylphosponium tosylate arereacted with 0.32 g (1 mmol) of6-formyl-7-(4-methoxycarbonylphenyl)-5-thiaheptanoic acid methyl esterfollowing the same procedure as in Example 67. 0.18 of the product arethus obtained.

Yield: 32% of theory

R_(f) -value: 0.16 (n-hexane:ether 7:3).

NMR (CDCl₃, 300 MHz): 1.85 [2] quintet, J=8 Hz, 2.25 [2] quintet, J=8Hz, 2.35 [2] tr, J=8 Hz, 2.4-2.6 [2] m, 2.7 [1] dd, J=14 Hz, J=10 Hz,3.0 [1] dd, J=14 Hz, J=8 Hz, 3.05 [1] dd, J=14 Hz, J=8 Hz, 3.2 [1] dd,J=14 Hz, J=8 Hz, 3.65 [3] s, 3.9 [3] s, 3.95 [1] tr, d, J=10 Hz, J=8 Hz,4.1-4.2 [4] m, 5.4 [1] tr, J=8 Hz, 5.65 [1] d, tr, J=10 Hz, J=8 Hz,6.15-7.0 [6] m, 7.1 [1] tr, J=8 Hz, 7.2-7.35 [4] m, 7.9 [2] d, J=8 Hz.

EXAMPLE 806-(4-Carboxybenzyl)-9-[2-(3-phenoxypropoxy)phenyl]-5-thia-7(Z)-nonenoicacid ##STR79##

0.17 g of the product obtained in Example 78 are saponified followingthe same procedure as in Example 68. 90 mg of a solid product are thusobtained.

Yield: 55.7% of theory

R_(f) -value: 0.32 (methylenechloride:methanol 95:5)

NMR (CDCl₃, 300 MHz): 1.8-1.95 [2] m, 2.25 [2] quinetet, J=8 Hz,2.35-2.6 [4] m, 2.8 [1] dd, J=14 Hz, J=10 Hz, 3.0 [1] dd, J=14 Hz, J=8Hz, 3.1 [1] dd, J=14 Hz, J=8 Hz, 3.25 [1] dd, J=14 Hz, J=8 Hz, 3.95 [1]tr, d, J=10 Hz, J=8 Hz, 4.1-4.2 [4] m, 5.35 [1] tr, J=10 Hz, 5.7 [1] d,tr, J=10 Hz, J=8 Hz, 6.2-7.0 [6] m, 7.1 [1] tr, d, J=8 Hz, J=1 Hz,7.2-7.35 [4] m, 8.0 [2] d, J=8 Hz.

EXAMPLE 816-(4-Methoxycarbonylbenzyl)-9-[4-(3-phenoxypropoxy)phenyl]-5-thia-7(Z)-nonenoicacid methyl ester ##STR80## 0.84 g 81.2 mmol) of2-[4-(3-phenoxypropoxy)phenyl]ethyltriphenylphosphoniumtosylate arereacted with 0.32 g (1 mmol) of6-formyl-7-(4-methoxycarbonylphenyl)-5-thiaheptanoic acid methyl esterfollowing the same procedure as in Example 67. 0.11 g of the product arethus obtained.

Yield: 19.5% of theory

R_(f) -value: 0.16 (n-hexane:ether 7:3)

NMR (CDCl₃, 300 MHz): 1.9 [2] quintet, J=8 Hz, 2.25 [2] quintet, J=8 Hz,2.35-2.65 [4] m, 2.8 [1] dd, J=14 Hz, J=10 Hz, 3.0-3.1 [3] m, 3.7 [3] s,3.9 [3] s, 3.9-4.0 [1] m, 4.05-4.2 [4] m, 5.3 [1] tr, J=10 Hz, 5.6 [1]tr, d, J=10 Hz, J=8 Hz, 6.2 [3] s, 6.9-7.0 [3] m, 7.25-7.4 [5] m, 7.95[2] d, J=8 Hz.

EXAMPLE 826-(4-Carboxybenzyl)-9-[4-(3-phenoxypropoxy)phenyl]-5-thia-7(Z)-nonenoicacid ##STR81##

80 mg of the product obtained in Example 80 are saponified following thesame procedure as in Example 68. 70 mg of the product are thus obtained.

Yield: 92.2% of theory

NMR (CDCl₃, 300 MHz): 1.9 [2] quintet, J=8 Hz, 2,25 [2] quintet, J=8 Hz,2.4 [2] tr, J=8 Hz, 2.45-2.65 [2] m, 2.8 [1] dd, J=14 Hz, J=10 Hz,3.0-3.1 [3] m, 3.95 [1] tr, d, J=10 Hz, J=8 Hz, 4.1-4, [4] m, 5.3 [1]tr, J=10 Hz, 5.55 [1] d, tr, J=10 Hz, J=8 Hz, 6.15-6.25 [3] m, 6.9-7.0[3] m, 7.25-7.3 [4] m, 8.0 [2] d, J=8 Hz.

EXAMPLE 836-(4-Methoxycarbonylbenzyl)-9-[2-(3-phenoxypropoxy)phenyl]-7(Z)-nonenoicacid methyl ester ##STR82##

0.84 g (1.2 mmol) of2-[2-(3-phenoxypropoxy)phenyl]ethyltriphenylphosphonium tosylate arereacted with 0.31 g (1 mmol) of6-formyl-7-(4-methoxycarbonylphenyl)heptanoic acid methyl esterfollowing the same procedure as in Example 67. 0.28 g of the product arethus obtained.

Yield: 51.4% of theory

R_(f) -value: 0.31 (n-hexane:ether 7:3)

NMR (CDCl₃, 300 MHz): 1.2-1.65 [6] m, 2.3-2.4 [4] m, 2.55 [1] dd, J=14Hz, J=10 Hz, 2.65-2.8 [2] m, 3.0 [1] dd, J=14 Hz, J=8 Hz, 3.15 [1] dd,J=14 Hz, J=8 Hz, 3.65 [3] s, 3.9 [3] s, 4.1-4.2 [4] m, 5.2 [1] tr, J=10Hz, 5.55 [1] tr, d, J=10 Hz, J=8 Hz, 6.7-7.0 [6] m, 7.05-7.15 [1] m, 7.2[2] d, J=8 Hz, 7.25 [2] d, J=8 Hz, 7.9 [2] d, J=8 Hz.

EXAMPLE 846-(4-Carboxybenzyl)-9-[2-(3-phenoxypropoxy)phenyl]-7-(Z)-nonenoic acid##STR83##

0.25 g of the product obtained in Example 78 are reacted following thesame procedure as in Example 68. 0.21 g of the product are thusobtained.

Yield: 88.6% of theory

R_(f) -value: 0.44 (methylenechloride:methanol 95:5)

NMR (CDCl₃, 300 MHz): 1.2-1.7 [6] m, 2.2-2.4 [4] m, 2.55 [1] dd, J=14Hz, J=10 Hz, 2.65-2.8 [2] m, 3.0 [1] dd, J=14 Hz, J=8 Hz, 3.15 [1] dd,J=14 Hz, J=8 Hz, 4.05-4.2 [4] m, 5.2 [1] tr, J=10 Hz, 5.55 [1] d, tr,J=10 Hz, J=8 Hz, 6.7-7.0 [6] m, 7.05-7.35 [5], 7.95 [2] d, J=8 Hz.

EXAMPLE 856-(4-Methoxycarbonylbenzyl)-9-[4-(3-phenoxypropoxy)phenyl]-7-(Z)-nonenoicacid methyl ester ##STR84##

0.84 g (1.2 mmol) of2-[4-(3-phenoxypropoxy)phenyl]ethyltriphenylphosphoniumtosylate arereacted with 0.31 g (1 mmol) of6-formyl-7-(4-methoxycarbonylphenyl)heptanoic acid methylester followingthe same procedure as in Example 67. 0.12 g of the product are thusobtained.

Yield: 22% of theory

R_(f) -value: 0.26 (n-hexane:ether 7:3)

NMR (CDCl₃, 300 MHz): 1.2-1.7 [6] m, 2.2-2.4 [4] m, 2.55 [1] dd, J=14Hz, J=10 Hz, 2.65-2.8 [2] m, 2.9-3.1 [2] m, 3.65 [3] s, 3.9 [3] s,4.1-4.2 [4] m, 5.2 [1] tr, J=10 Hz, 5.5 [1] d, tr, J=10 Hz, J=8 Hz,6.7-6.8 [3] m, 6.9-7.0 [3] m, 7.15-7.3 [5] m, 7.9 [2] d, J=8 Hz.

EXAMPLE 866-(4-Carboxybenzyl)-9-[4-(3-phenoxypropoxy)phenyl]-7(Z)-nonenoic acid##STR85##

0.11 g of the product obtained in Example 80 are reacted following thesame procedure as in Example 68. 0.1 g of the product are thus obtained.

Yield: 95.8% of theory

NMR (CDCl₃, 300 MHz): 1.2-1.7 [6] m, 2.25 [2] quintet, J=8 Hz, 2.35 [2]tr, J=8 Hz, 2.55 [1] dd, J=14 Hz, J=10 Hz, 2.65-2.8 [2] m, 2.95-3.1 [[2]m, 4.05-4.15 [4] m, 5.2 [1] tr, J=10 Hz, 5.5 [1] d, tr, J=10 Hz, J=8 Hz,6.7-6.8 [3] m, 6.85-6.95 [3] m, 7.2-7.3 [5] m, 8.0 [2] d, J=8 Hz.

EXAMPLES 87 AND 886-(4-Methoxycarbonylbenzyl)-8-[4-(4-phenoxybutoxy)phenyl]-7(E)-octenoicacid methyl ester (trans-isomer) ##STR86##6-(4-Methoxycarbonylbenzyl)-8-[4-(4-phenoxybutoxy)phenyl]-7(Z)-octenoicacid methylester (cis-isomer) ##STR87##

0.79 ml (1 mmol of n-butyllithium in hexane (content titrated) are addeddropwise at -25° C., under nitrogen to a solution of 0.72 g (1.2 mmol)of 4-(4-phenoxybutoxy)benzyltriphenylphosphonium bromide in 10 ml ofabsolute tetrahydrofuran. The reaction solution is subsequently stirredfor 10 minutes at -25° C. and cooled to -70° C. Then at -70° C. 1.8 mlof absolute DMPU are added dropwise followed by a solution of 0.31 g (1mmol) of 6-formyl-7-(4-methoxycarbonylphenyl)heptanoic acid methyl esterin 2 ml of absolute tetrahydrofuran. The mixture is subsequently stirredat -70° C. for 30 minutes, 0.5 ml of methanol are then added and themixture is heated slowly to 0° C. After stirring for 30 mins. at 0° C.the mixture is diluted with water and extracted with ethylacetate. Theorganic phase is washed with water and a saturated sodium chloridesolution, dried with sodium sulphate and concentrated by evaporation.The residue is chromatographed with hexane/ether 9/1 and 8/2 on 50 g ofsilica gel (Merck Si 60, 0.04-0.063 mm). 2 fractions are thus obtained,the second of which contains the pure trans-isomer. The first fractioncontains a mixture of the cis- and the trans-isomer and after beingconcentrated by evaporation is once again chromatographed withhexane/ether 70/30 on 250 g of silica gel. 2 fractions are thus obtainedof which the first, after being concentrated by evaporation, yields 60mg of the pure cis-isomer. After concentration by evaporation of thesecond fraction, together with the second fraction from the firstchromatographic process, 0.29 g of the pure trans-isomer are obtained.

Yield: 11% of theory of the cis-isomer. 53% of theory of thetrans-isomer.

R_(f) -value: 0.27 for the cis-isomer (n-hexane:ether 7:3). 0.21 for thetrans-isomer (n-hexane:ether 7:3).

NMR (CDCl₃, 300 MHz) of the cis-isomer: 1.2-1.7 [6] m, 1.95-2.0 [4] m,2.25 [2] tr, J=8 Hz, 2.6-2.8 [2] m, 2.85-3.9 [1] m, 3.65 [3] s, 3.9 [3]s, 4.0-4.1 [4] m, 5.3 [1] tr, J=10 Hz, 6.4 [1] d, J=10 Hz, 6.7-7.0 [7]m, 7.1-7.3 [4] m, 7.9 [2] d, J=8 Hz. Of the trans-isomer: 1.2-1.7 [6] m,1.95-2.0 [4] m, 2.25 [2] tr, J=8 Hz, 2.35-2.45 [1] m, 2.65-2.85 [2] m,3.65 [3] s, 3.9 [3] s, 4.0-4,1 [4] m, 5.8 [1] dd, J=14 Hz, J=8 Hz, 6.15[1] d, J=14 Hz, 6.85-6.95 [3] m, 7.2-7.35 [6] m, 7.95 [2] d, J=8 Hz.

EXAMPLE 896-(4-Carboxybenzyl)-8-[4-(4-phenoxybutoxy)phenyl]-7(E)-octenoic acid##STR88##

0.24 g of the product obtained in Example 87 (trans-isomer) aresaponified following the same procedure as in Example 68. 0.2 g of theproduct are thus obtained.

Yield: 87.8% of theory

NMR (CDCl₃, 300 MHz): 1.2-1.7 [6] m, 1.95 [4] s, 2.3 [2] tr, J=8 Hz,2.35-2.5 [1] m, 2.7-2.8 [2] m, 3.95-4.05 [4] m, 5.8 [1] dd, J=14 Hz, J=8Hz, 6.2 [1] d, J=14 Hz, 6.8 [2] d, J=8 Hz, 6.85-7.0 [3] m, 7.15-7.3 [6]m, 8.0 [2] d, J=8 Hz.

EXAMPLE 906-(4-Carboxybenzyl)-8-[4-(4-phenoxybutoxy)phenyl]-7(Z)-octenoic acid##STR89##

50 mg of the compound obtained in Example 88 (cis-isomer) are saponifiedfollowing the same procedure as in Example 68. 40 mg of the product arethus obtained.

Yield: 84.2% of theory

NMR (CDCl₃, 300 MHz): 1.2-1.7 [6] m, 1.95-2.0 [4] m, 2.3 [2] tr, J=8 Hz,2.6-2.8 [2] m, 2.85-3.0 [1] m, 3.95-4.05 [4] m, 5.3 [1] tr, J=10 Hz 6.35[1] d, J=10 Hz, 6.75 [2] d, J=8 Hz, 6.85-7.0 [5] m, 7.2 [2] d, J=8 Hz,7.2-7.3 [2] m, 7.95 [2] d, J=8 Hz.

EXAMPLES 91 AND 926-(4-Methoxycarbonylbenzyl)-8-[3-(4-phenoxybutoxy)phenyl]-7(E)-octenoicacid methylester (trans-isomer) ##STR90##6-(4-Methoxycarbonylbenzyl)-8-[3-(4-phenoxybutoxy)phenyl]-7(Z)-octenoicacid methylester (cis-isomer) ##STR91##

0.72 g (1.2 mmol) of 3-(4-phenoxybutoxy)benzyltriphenylphosphoniumbromide are reacted with 0.31 g (1 mmol) of6-formyl-7-(4-methoxycarbonyl)heptanoic acid methyl ester andchromatographed following the same procedure as in Examples 87 and 88.58.8 mg of the cis-isomer and 0.32 g of the trans-isomer are thusobtained.

Yield: 10.8% of theory of the cis-isomer and 58.7% of theory of thetrans-isomer

R_(f) -value: 0,29 for the cis-isomer (n-hexane:ether 7:3) 0,25 for thetrans-isomer (n-hexane:ether 7:3)

NMR (CDCl₃, 300 MHz) of the cis-isomer: 1.15-1.6 [6] m, 1.9-2.0 [4] m,2.25 [2] tr, J=8 Hz, 2.6-2.8 [2] m, 2.8-3.0 [1] m, 3.65 [3] s, 3.9 [3]s, 3.95 [2] tr, J=8 Hz, 4.05 [2] tr, J=8 hz, 5.35 [1] tr, J=10 Hz, 6.4[1] d, J=10 Hz, 6.45 [1] s, 6.55 [1] d, J=8 Hz, 6.75 [1] dd, J=8 Hz, J=1Hz, 6.9-7.0 [3] m, 7.1-7.3 [5] m, 7.9 [2] d, J=8 Hz. Of thetrans-isomer: 1.25-1.7 [6] m, 1.95-2.05 [4] m, 2.25 [2] tr, J=8 Hz,2.4-2.55 [1] m, 2.7-2.9 [2] m, 3.65 [3] s, 3.9 [3] s, 4.0-4.1 [4] m,5.95 [1] dd, J=14 Hz, J=10 Hz, 6.15 [1] d, J=14 Hz, 6.75 [1] dd, J=8 Hz,J=1 Hz, 6.8-7.0 [5] m, 7.15-7.35 [5] m, 7.9 [2] d, J=8 Hz.

EXAMPLE 936-(4-Carboxybenzyl)-8-[3-(4-phenoxybutoxy)phenyl]-7(Z)-octenoic acid##STR92##

60 mg of the compound obtained in Example 92 (cis-isomer) are saponifiedfollowing the same procedure as in Example 68. 30 mg of the product arethus obtained.

Yield: 52.8% of theory

NMR (CDCl₃, 300 mHz): 1.15-1.6 [6] m, 1.9-2.0 [4] m, 2.2 [2] tr, J=8 Hz,2.6-2.8 [2] m, 2.85-3.0 [1] m, 3.9 [2] s, wide, 4.05 [2] s, wide, 5.4[1] tr, J=10 Hz, 6.4 [1] d, J=10 Hz, 6.45 [1] s, 6.55 [1] d, J=8 Hz, 6.7[1] dd, J=8 Hz, J=1 Hz, 6.85-6.95 [3] m, 7.1-7.3 [5] m, 7.9 [2] d, J=8Hz.

EXAMPLE 946-(4-Carboxybenzyl)-8-[3-(4-phenoxybutoxy)phenyl]-7(E)-octenoic acid##STR93##

0.35 g of the compound obtained in Example 91 (trans-isomer) aresaponified following the same procedure as in Example 68. 0.28 g of theproduct are thus obtained.

Yield: 84.3% of theory

NMR (CDCl₃, 300 MHz): 1.25-1.7 [6] m, 1.95 [4] s, 2.3 [2] tr, J=8 Hz,2.4-2.55 [1] m, 2.75 [2] d, J=8 Hz, 4.05 [4] s, 5.95 [1] dd, J=14 Hz,J=8 Hz, 6.2 [1] d, J=14 Hz, 6.7 [1] dd, J=8 Hz, J=1 Hz, 6.8-7.0 [5] m,7.15-7.35 [5] m, 8.0 [2] d, J=8 Hz.

EXAMPLES 95 AND 966-(4-Methoxycarbonylbenzyl)-8-[4-(4-phenoxybutoxy)phenyl]-5-thia-7(E)-octenoicacid methylester (trans-isomer) ##STR94##6-(4-Methoxycarbonylbenzyl)-8-[4-(4-phenoxybutoxy)phenyl]-5-thia-7(Z)-octenoicacid methylester (cis-isomer) ##STR95##

0.72 g (1.2 mmol) of 4-(4-phenoxybutoxy)benzyltriphenylphosphoniumbromide are reacted with 0.32 g (1 mmol) of6-formyl-7-(4-methoxycarbonylphenyl)-5-thiaheptanoic acid methyl esterand chromatographed following the same procedure as in Examples 87 and88. 18.6 mg of the cis-isomer and 0.26 g of the trans-isomer are thusobtained.

Yield: 3.3% of theory of the cis-isomer 46.2% of theory of thetrans-isomer

R_(f) -value: 0.22 for the cis-isomer (n-hexane:ether 7:3) 0.15 for thetrans-isomer (n-hexane:ether 7:3)

NMR (CDCl₃, 300 MHz) of the cis-isomer: 1.55-17 [2] m, 1.9-2.0 [4] m,2.25 [2] tr, J=8 Hz, 2.4 [2] tr, J=8 Hz, 2.95 [1] dd, J=14 Hz, J=10 Hz,3.05 [1] dd, J=14 Hz, J=8 Hz, 3.6 [3] s, 3.9 [3] s, 3.95-4.15 [5] m, 5.4[1] tr, J=10 Hz, 6.5 [1] d, J=10 Hz, 6.7-7.0 [7] m, 7.25-7.35 [4] m,7.95 [2] d, J=8 Hz. Of the trans-isomer: 1.75-2.0 [6] m, 2.3-2.6 [4] m,2.95-3.1 [2] m, 3.6 [1] q, J=8 Hz, 3.65 [3] s, 3.9 [3] s, 4.05 [4] swide, 5.85 [1] dd, J=14 Hz, J=8 Hz, 6.2 [1] d, J=14 Hz, 6.8 [2] d, J=8Hz, 6.85-7.0 [3] m, 7.95 [2] d, J=8 Hz.

EXAMPLE 976-(4-Carboxybenzyl)-8-[4-(4-phenoxybutoxy)phenyl]-5-thia-7(E)-octenoicacid ##STR96##

0.27 g of the compound obtained in Example 95 (trans-isomer) aresaponified following the same procedure as in Example 68. 0.22 g of theproduct are thus obtained.

Yield: 85.7% of theory

NMR (CDCl₃, 300 MHz): 1.75-2.05 [6] m, 2.25-2.6 [4] m, 2.9-3.1 [2] m,3.6 [1] q, J=8 Hz, 4.0 [4] s, 5.85 [1] dd, J=14 Hz, J=8 Hz, 6.2 [1] d,J=14 Hz, 6.8-7.0 [5] m, 7.2-7.3 [6] m, 7.95 [2] d, J=8 Hz.

EXAMPLE 986-(4-Carboxybenzyl)-8-[4-(4-phenoxybutoxy)phenyl]-5-thia-7(Z)-octenoicacid ##STR97##

18 mg of the compound obtained in Example 96 (cis-isomer) are saponifiedfollowing the same procedure as in Example 68. 15.6 mg of the productare thus obtained.

Yield: 91.2% of theory

NMR (CDCl₃, 300 MHz): 1.6 [2] quintet, J=8 Hz, 2.9 [4] s wide, 2.3 [2]tr, J=8 Hz, 2.4 [2] tr, J=8 Hz, 2.9-3.1 [2] m, 3.9-4.15 [5] m, 5.4 [1]tr, J=10 Hz, 6.5 [1] d, J=10 Hz, 6.7-7.0 [7] m, 7.2-7.35 [4] m, 8.0 [2]d, J=8 Hz.

EXAMPLES 99 AND 1006-(4-methoxycarbonylbenzyl)-8-[3-(4-phenoxybutoxy)phenyl]-5-thia-7(Z)-octenoicacid methyl ester (cis-isomer) ##STR98## and6-(4-methoxycarbonylbenzyl)-8-[3-(4-phenoxybutoxy)phenyl]-5-thia-7-(E)-octenoicacid methyl ester (trans-isomer) ##STR99##

0.72 g (1.2 mmol) of 3-(4-phenoxybutoxy)benzyltriphenylphosphoniumbromide, are reacted with 0.32 g (1 mmol) of6-formyl-7-(4-methoxycarbonylphenyl)-5-thiaheptanoic acid methyl esterfollowing the same procedure as in 87 and 88, 19.6 mg of the cis-isomerand 0.34 g of the trans-isomer are thus obtained.

Yield: 3.5% of theory of the cis-isomer and 60.4% of theory of thetrans-isomer

R_(f) -value: 0.2 for the cis-isomer (n-hexane ether 7:3). 0.6 for thetrans-isomer (n-hexane ether 7.3).

NMR (CDCl₃, 300 MHz) of the cis-isomer: 1.5-1.7 [2] m, 1.9-2.0 [4] m,2.2 [2] tr, J=8 Hz, 2.4 [2] tr, J=8 Hz, 2.9 [1] dd, J=14 Hz, J=10 Hz,3.05 [1] dd, J=14 Hz, J=8 Hz, 3.6 [3] s, 3.9 [5] s wide, 4.0-4.15 [39 m,5.5 [1] dr, J=10 Hz, 6.35 [1] s, 6.45 [1] d, J=8 Hz, 6.5 [1] d, J=10 Hz,6.7 [1] dd, J=8 Hz, J=1 Hz, 6.85-7.0 [3] m, 7.1 [1] tr, J=8 Hz,7.25-7.35 [4] m, 7.95 [2] d, J=8 Hz. of the trans-isomer: 1.75-2.05 [6]m, 2.3-2.65 [4] m, 2.95-3.1 [2] m, 3.6 [1] q, J=8 Hz, 3.65 [3] s, 3.9[3] s, 4.05 [4] s wide, 6.0 [1] dd, J=14 Hz, J=8 Hz, 6.2 [1] d, J=14 Hz,6.7 [1] dd, J=8 Hz, J=14 Hz, 6.8-7.0 [5] m, 7.2 [1] tr, J=8 Hz,7.25-7.35 [4] m, 7.95 [2] d, J=8 Hz.

EXAMPLE 1016-(4-Carboxybenzyl)-8-[3-(4-phenoxybutoxy)phenyl]-5-thia-7(Z)-octenoicacid ##STR100##

19 mg of the compound obtained in Example 99 (cis-isomer) are saponifiedfollowing the same procedure as in Example 68. 18 mg of the product arethus obtained. Yield: 99% of theory.

NMR (CDCl₃, 300 MHz): 1.6 [2] quintet, J=8 Hz, 1.95 [4] s wide, 2.25 [2]tr, J=8 Hz, 2.4 [2] tr, J=8 Hz, 2.9-3.1 [2] m, 3.9 [2] s, wide, 4.0-4.1[3] m, 5.5 [1] tr, J=10 Hz, 6.4 [1] s, 6.5 [1] d, J=8 Hz, 6.55 [1] d,J=14 Hz, 6.7 [1] dd, J=8 Hz, J=1 Hz, 6.85-7.0 [3] m, 7.15 [1] tr, J=8Hz, 7.2-7.35 [4] m, 8.0 [2] d, J=8 Hz.

EXAMPLE 1026-(4-Carboxybenzyl)-8-[3-(4-phenoxybutoxy)phenyl]-5-thia-7(E)-octenoicacid ##STR101##

0.38 g of the compound obtained in Example 100 (trans-isomer) aresaponified following the same procedure as in Example 68. 0.29 g of theproduct are obtained.

Yield: 80.4% of the theory

NMR (CDCl₃, 300 MHz): 1.75-2.05 [6] m, 2.25-2.6 [4] m, 2.9-3.1 [2] m,3.6 [1] q, J=8 Hz, 4.05 [4] s wide, 6.0 [1] dd, J=14 Hz, J=8 Hz, 6.2 [1]d, J=14 Hz, 6.75 [1] dd, J=8 Hz, J=1 Hz, 6.8-7.0 [5] m, 7.2 [1] tr, J=8Hz, 7.25-7.35 [4] m, 7.95 [2] d, J=8 Hz.

EXAMPLE 1036-(4-Methoxycarbonylbenzyl)-8-[2-(4-phenoxybutoxy)phenyl]-5-thia-7(E)-octenoicacid methyl ester ##STR102##

0.72 g (1.2 mmol) of 2-(4-phenoxybutoxy)benzyltriphenylphosphoniumbromide are reacted with 0.32 g (1 mmol) of6-formyl-7-(4-methoxycarbonylphenyl)-5-thiaheptanoic acid methyl esterfollowing the same procedure as in Examples 87 and 88. 0.22 of thetrans-isomer are thus obtained.

Yield: 51.5% of theory

R_(f) -value: 0.22 (n-hexane:ether 7:3)

NMR (CDCl₃, 300 MHz): 1.75-2.05 [6] m, 2.3-2.65 [4] m, 3.0 [2] d, J=8Hz, 3.6 [3] s, 3.65 [1] q, J=8 Hz, 3.9 [3] s, 4.05 [4] tr, J=7 Hz, 6.0[1] dd, J=14 Hz, J=8 Hz, 6.55 [1] d, J=14 Hz, 6.8-7.0 [5] m, 7.1-7.35[5] m, 7.4 [1] d, J=8 Hz, 7.95 [2] d, J=8 Hz.

EXAMPLE 1046-(4-Carboxybenzyl)-8-[2-(4-phenoxybutoxy)phenyl]-5-thia-7(E)-octenoicacid ##STR103##

0.29 g of the compound obtained in Example 103 are saponified followingthe same procedure as in Example 68. 0.1 g of the product are thusobtained.

Yield: 39.9% of theory.

NMR (CDCl₃, 300 MHz): 1.75-2.0 [6] m, 2.25-2.6 [4] m, 2.95-3.05 [2] m,3.65 [1] q, J=8 Hz, 3.95-4.05 [4] m, 6.0 [1] dd, J=14 Hz, J=8 Hz, 6.55[1] d, J=8 Hz, 6.8-7.0 [5] m, 7.1-7,35 [5] m, 7.4 [1] d, J=8 Hz, 7.95[2] d, J=8 Hz.

EXAMPLE 1056-(4-Methoxycarbonylbenzyl)-8-[2-(4-phenoxybutoxy)phenyl]-7(E)-octenoicacid methyl ester ##STR104##

0.72 g (1.2 mmol) of 2-(4-(phenoxybutoxy)benzyltriphenylphosphoniumbromide are reacted with 0.31 g (1 mmol) of6-formyl-7-(4-methoxycarbonylphenyl) -methoxycarbonylphenyl)heptanoicacid methyl ester following the same procedure as in Examples 87 and 88.Only the trans-isomer is isolated, of which 0.4 g are obtained.

Yield: 73.4% of theory

R_(f) -value: 0.32 (n-hexane:ether 7:3)

NMR (CDCl₃, 300 MHz): 1.2-1.7 [6] m, 1.9-2.0 [4] m, 2.25 [2] tr, J=8 Hz,2.4-2.55 [1] m, 2.7-2.9 [2] m, 3.6 [3] s, 3.9 [3], 3.95-4.05 [4] m, 6.0[1] dd, J=14 Hz, J=8 Hz, 6.55 [1] d, J=14 Hz, 6.7-7.0 [5] m, 7.1-7.3 [5]m, 7.35 [1] d, J=8 Hz, 7.95 [2] d, J=8 Hz.

EXAMPLE 1066-(4-Carboxybenzyl)-8-[2-(4-phenoxybutoxy)phenyl]-7(E)-octenoic acid##STR105## 0.4 g of the compound obtained in Example 105 are saponifiedfollowing of the same procedure as in Example 68. 0.35 g of the productare thus obtained.

Yield: 92.3% of theory

NMR (CDCl₃, 300 MHz): 1.2-1.7 [6] m, 1.9-2.0 [4] m, 2.3 [2] tr, J=8 Hz,2.4-2.55 [1] m, 2.7-2.75 [29 m, 3.95-4.05 [4] m, 5.95 [1] dd, J=14 Hz,J=8 Hz, 6.55 [1] d, J=14 Hz, 6.7-7.0 [5] m, 7.1-7.3 [5] m, 7.35 [1] d,J=8 Hz, 8.0 [2] d, J=8 Hz.

EXAMPLE 1076-(4-Methoxycarbonylphenyl)-9-[4-(3-phenoxypropoxy)phenyl]-7(Z)-nonenoicacid methyl ester ##STR106##

0.47 g (0.6 mmol) of2-[4-(3-phenoxypropoxy)phenyl]ethyltriphenylphosphonium are reacted with0.15 g (0.5 mmol) or 6-formyl-6-(4methoxycarbonylphenyl)-hexanoic acidmethyl ester following the same procedure as in Example 67. 10.7 mg ofthe product are thus obtained.

Yield: 4% of theory

R)_(f) -value: 0.49 (n-hexane:ether 1:1)

NMR (CDCl₃, 300 MHz): 1.2-1.7 [6] m, 2.2-2.4 [49 m, 3.4 [2] d, J=8 Hz,3.65 [3] s, 3.75 [1] q, J=8 Hz, 3.9 [3] s, 4.1-4.2 [4] m, 5.55-5.65 [2]m, 6.7-7.0 [6] m, 7.2-7.35 [5, 8.0 [2] d, J=8 Hz.

EXAMPLE 1086-(4-Carboxyphenyl)-9-[4-(3phenoxypropoxy)phenyl]-7(Z)-nonenoic acid##STR107##

10.7 mg of the compound obtained in Example 107 are saponified followingthe same procedure as in Example 68. 8.6 mg of the product are thusobtained.

Yield: 85.6% of theory

NMR (CDCl₃, 300 MHz): 1.2-1.7 [6] m, 2.2-2.4 [4] m, 3.4 [2] m, 3.8 [1]q, J=8 Hz, 4.1-4.2 [4] m, 5.05-5.2 [2] m, 6.7-7.0 [6] m, 7.2-7.4 [5] m,8.0 [2] d, J=8 Hz.

EXAMPLE 109 6-(4-Ehtoxycarbonylbenzyl)-7(Z),10(Z)-hexadecadienoic acidethyl ester ##STR108##

0.67 g (1.2 mmol) of 3(Z)-nonenyltriphenyl- of7-(4-ethoxycarbonylphenyl)-6-formylheptanoicacid ethyl ester andchromatographed following the same procedure as in Example 67. 0.3 g ofoily product are thus obtained.

Yield: 68% of theory

R_(f) -value: 0.39 (n-hexane:ether 85:15).

NMR (CDCl₃, 300 MHz): 0.9 [3] tr, J=8 Hz, 1.2-1.7 [18] m, 1.9 [2] q, J=8Hz, 2.25 [2] tr, J=8 Hz, 2.35-2.8 [5] m, 4.1 [2] q, J=8 Hz, 4.35 [2] q,J=8 Hz, 5.0-5.15 [2] m, 5.25-5.35 [2] m, 7.2 [2] d, J=8 Hz, 7.9 [2] d,J=8 Hz.

EXAMPLE 110 6-(4-Carboxybenzyl)-7(Z),10(Z)-hexadecadienoic acid##STR109##

0.3 g of the compound obtained in Example 104 are saponified followingthe same procedure as in Example 68. 0.2 g of a solid product are thusobtained.

Yield: 76% of theory

R_(f) -value: 0.41 (methylene chloride:methanol 95:5)

NMR (CDCl₃, 250 MHz): 0.9 [3] tr, J=8 Hz, 1.2-1.7 [12] m, 1.9 [2] q, J=8Hz, 2.3-2.8 [7] m, 5.0-5.15 [2] m, 5.25-5.4 [2] m, 7.25 [2] d, J=8 Hz,8.0 [2] d, J=8 Hz.

EXAMPLES 111 and 1126-(4-Methoxycarbonylbenzyl)-8-[3-(5-phenoxypentyl)phenyl]7(Z)-octenoicacid methyl ester(cis-isomer) ##STR110##6-(4-methoxycarbonylbenzyl)-8-[3-(5-phenoxypentyl)phenyl-7(E)-octenoicacid methyl ester (trans-isomer) ##STR111##

299.6 mg (0.5 mmol) of 3-(5-phenoxypent-1-yl)benzyltriphenylphosphoniumbromide are reacted with 0.17 g (0.555 mmol) of6-formyl-7-(4-methoxycarbonylphenyl)heptanoic acid methyl ester andchromatographed following the same procedure as in Examples 87 and 88.32 mg of the cis-isomer and 134 mg of the trans-isomer are thusobtained.

Yield: 13% of theory of the cis-isomer.

53% of theory of the trans-isomer.

R_(f) -value: 0.35 for the cis-isomer (n-hexane:ethyl-acetate 8.2). 0.30for the trans-isomer (n-hexane:ethyl-acetate 8:2).

NMR (CDCl₃, 300 MHz) of the cis-isomer: 1.15-1.7 [10] m, 1.7 [2]quintet, J=8 Hz, 2.2 [2] tr, J=8 Hz, 2.55 [2] tr, J=8 Hz, 2.6-2.8 [2] m,2.8-2.95 [1] m, 3.65 [3] s, 3.9 [3] s, 3.95 [2] tr, J=8 Hz, 5.35 [1] tr,J=10 Hz, 6.4 [1] d, J=10 Hz, 6.65 [1] s, 6.8 [1] d, J=8 Hz, 6.85-7.0 [4]m, 7.1-7.2 [3] m, 7.25-7.35 [2] m, 7.9 [2] d, J=8 Hz. Of thetrans-isomer: 1.2-1.75 [10] m, 1.8 [2] quintet, J=8 Hz, 2.25 [2] tr, J=8Hz, 2.4-2.55 [1] m, 2.6 [2] tr, J=8 Hz, 2.7-2.85 [2] m, 3.65 [3] s, 3.9[3] s, 3.95 [2] tr, J=8 Hz, 5.95 [1] dd, J=14 Hz, J=8 Hz, 6.2 [1] d,J=14 Hz, 6.85-6.95 [3] m, 7.0 [1] d, J=8 Hz, 7.05-7.3 [7] m, 7.9 [2] d,J=8 Hz.

EXAMPLE 1136-(4-Carboxybenzyl)-8-[3-(5-phenoxypentyl)phenyl]-7(E)-octenoic acid##STR112##

8.25 mg of the compound obtained in Example 111 (trans-isomer) aresaponified following the same procedure as in Example 68. 74 mg of theproduct are thus obtained.

Yield: 92% of theory

R_(f) -value: 0.65 (mobile solvent:organic phase of a vigorously shakenmixture of 44 ml of ethyl-acetate, 8 ml of glacial acetic acid, 20 ml ofisooctane and 40 ml of water).

NMR (CDCl₃, 300 MHz): 1.2-1.7 [10] m, 1.8 [2] quintet, J=8 Hz, 2.3 [2]tr, J=8 Hz, 2.4-2.55 [1] m, 2.6 [2] tr, J=8 Hz, 2.7-2.85 [2] m, 3.95 [2]tr, J=8 Hz, 5.95 [1] dd, J=14 Hz, 6.2 [1] d, J=14 Hz, 6.8-6.95 [3] m,7.0 [1] d, J=8 Hz, 7.1-7.3 [7] m, 8.0 [2] d, J=8 Hz.

EXAMPLE 1146-(4-Carboxybenzyl)-8-[3-(5-phenoxypentyl)phenyl]-7(Z)-octenoic acid##STR113##

20 mg of the compound obtained in Example 112 (cis-isomer) aresaponified following the same procedure as in Example 68. 16.5 mg of theproduct are thus obtained.

Yield: 87% of theory

R_(f) -value: 0.67 (mobile solvent: organic phase of a vigorously shakenmixture of 44 ml or ethyl-acetate, 8 ml of glacial acetic acid, 20 ml ofisooctane and 40 ml of water).

EXAMPLE 1156-(4-Methoxycarbonylbenzyl)-8-[4-(5-phenoxypentyl)phenyl]-7(E)-octenoicacid methyl ester ##STR114##

146.4 mg (0.25 mmol) of4-(5-phenoxypent-1-yl)-benzyltriphenylphosphonium bromide are reactedwith 77.2 mg (0.25 mmol) of 6-formyl-7-(4methoxycarbonylphenyl)heptanoicacid methyl ester and chromatographed following the same procedure as inExamples 87 and 88. 27 mg of the trans-isomer are thus obtained as theproduct in addition to a very small amount of the cis-isomer, which wasdiscarded.

Yield: 21% of theory

R_(f) -value: 0.13 (n-hexane: ethyl acetate 88:12)

NMR (CDCl₃, 300 MHz): 1.2-1.7 [10] m, 1.8 [2] quintet, J=8 Hz, 2.25 [2]tr, J=8 Hz, 2.35-2.5 [1] m, 2.6 [2] tr, J=8 Hz, 2.65-2.8 [2] m, 3.65 [3]s, 3.9 [3] s, 3.95 [2] tr, J=8 Hz, 5.9 [1] dd, J=14 Hz, J=8 Hz, 6.2 [1]d, J=14 Hz, 6.85-6.95 [3] m, 7.1 [2] d, J=8 Hz, 7.2-7.35 [6] m, 7.95 [2]d, J=8 Hz.

EXAMPLE 1166-(4-Carboxybenzyl)-8-[4-(5-phenoxypentyl)phenyl]-7(E)-octenoic acid##STR115##

15.3 mg of the compound obtained in Example 115 are saponified followingthe same procedure as in Example 68. 15.4 mg of the product are thusobtained.

Yield: 100% of theory

R_(f) -value: 0.67 (mobile solvent: organic phase of a vigorously shakenmixture of 44 ml of ethyl acetate, 8 ml of glacial acetic acid, 20 ml orisooctane and 40 ml of water).

EXAMPLE 1176-(4-Carboxybenzyl)-5-thia-7(E),9(E),11(z),14(z)-eicosatetraenoic acid5,5-dioxide

A solution of 0.37 (0.6 mmol) of oxone (2KHSO₅.KHSO₄.K₂ SO₄) in 3.7 mlof water was added to a solution of 30 mg (0.06 mmol) of6-(4-carboxybenzyl)-5-thia-7(E),9(E),11(z),14(z)-eicosatetraenoic acidin 120 ml of methanol-water (1:1) as it was stirred at 0° C. Theresultant solution was stirred overnight at 0° and the evaporated invacuo to remove the methanol. The resultant aqueous residue wasextracted twice with methylenechloride. The combined extracts were driedover sodium sulfate and then evaporated in vacuo. The residue waspurified by preparative HPLC on a Lichrosorb RP-8 (7 μm) column usingelution with acetonitrile/water/acetic acid (40:60:0.1) which had beenadjusted to pH 5.6 with concentrated aqueous ammonia. The product eluentwas evaporated in vacuo to remove most acetonitrile, then acidified with1N HCl and finally extracted with toluene. The product was dried oversodiumsulfate and evaporated in vacuo to yield 3 mg of purified product.

Yield: 9.2% of theory

HPLC: 2 minutes retention time:

Lichrosorb RP 18 (7 μm), 25 cm×4 mm, solvent as given above, 4.5ml/min., detection at 280 nm.

EXAMPLE 118 1-bromo-4-phenylbutane ##STR116##

15.0 g (0.1 mol) 4-phenylbutanol and 39.8 g (0.12 mol)carbontetrabromide were dissolved in 500 ml dry dichloromethane andcooled to 0° C., 36.7 g (0.14 mol) triphenylphosphine was then added andthe mixture stirred 1.5 hours under argon at 0° C. then evaporated invacuo. The resulting mixture was stirred in ether-hexane (1:1) andfiltered to remove insoluble material. The filtrate was then passedthrough a pad of silica gel and concentrated to give a pale yellowliquid 21.3 g.

Yield: 100% of theory

TLC R_(f) : 0.57 (ether-hexane 1:1)

NMR (CDCl₃, 60 MHz): 1.6-1.8[4]m, 2.55[2] t, J=7 Hz 3.3[2], t, J=7 Hz,7.2[5]s.

EXAMPLE 119 4-phenylbutyltriphenylphosphonium bromide ##STR117##

A solution of 10.65 g (50 mmol) 1-bromo-4-phenylbutane and 13.1 g (50mmol) triphenylphosphine in 100 ml acetonitrile was refluxed for 18hours under argon, then concentrated in vacuo. The residue wastriturated with ether and the resulting solid was collected byfiltration and washed with ether 20.7 g.

m.p.: 136°-138° C.

Yield: 87% of theory

TLC R_(f) : 0.30 (CH₂ Cl₂ :MeOH 9:1)

NMR (CDCl₃ 60 MHz): 1.6-2.0[4] m, 2.6[2], t, J=7 Hz, 3.6-4.0[2] m,7.0[5] s, 7.5-7.8[15] m.

EXAMPLE 120 1-(3-bromophenyl)-5-phenylpent-1(E)ene ##STR118##

Using the procedure of example 119 and 10.75 g (50 mmol)3-phenoxypropylbromide and 13.1 g (50 mmol) triphenylphosphine gave awhite solid m.p. 179.5°-180.5° C., 22.4 g.

Yield: 93% of theory

TLC R_(f) : 0.30 (CH₂ Cl₂ :MeOH 9:1)

NMR (CDCl₃, 60 MHz): 2.1[2] m, 3.7[2] m, 4.02[2] t, J=5 Hz, 6.7-7.2[5]m, 7.7[15] m.

EXAMPLE 121 1-(3-bromophenyl)-5-phenylpent-1(E)ene ##STR119##

9.6 g (20 mmol) 5-phenylpentyltriphenylphosphonium bromide in 120 ml drytetrahydrofuran was cooled to -78° C. under argon and 16.4 ml (20 mmol)n-butyllithium in hexane (content titrated) was added and the mixtureallowed to warm to -20° C. until a clear (orange) solution resulted.This was cooled to -78° C. and 2.4 ml (20 mmol) 3-bromobenzaldehyde wasadded. This was allowed to reach room temperature then diluted withwater and extracted twice with ether. The combined organic phases werewashed with saturated sodium chloride solution and concentrated invacuo. The residue was triturated with ether-hexane (1:1) and filteredto remove insoluble material. The filtrate was then filtered through apad of silica gel and concentrated in vacuo to give a yellow liquid 4.6g.

Yield: 76% of theory

TLC R_(f) : 0.53 (ether-hexane 1:1)

NMR (CDCl₃, 60 MHz): 1.65[2] t, J=7 Hz, 2.20[2] t, J=7 Hz, 2.52[2] t,J=7 Hz, 5.56[1] dt, J=12 Hz, J=7 Hz, 6.17[1] dt, J=12 Hz, J=1.5 Jz,6.9-7.4[9] m.

EXAMPLE 122 1-(3-bromophenyl)-4-phenoxybut-1(E)ene ##STR120##

Following the procedure of example 121 using the product of Example 120gave a pale yellow liquid 4.8 g.

Yield: 80% of theory

TLC R_(f) : 0.50 (ether-hexane 1:1)

NMR (CDCl₃, 60 MHz): 2.7[2] dd, J=6 Hz, J 1.5 Hz, 3.95[2] t, J=6 Hz,5.77[1] dt, J=12 Hz, J=6 Hz, 6.46[1] dt, J=12 Hz, J=1.5 Hz, 6.9-7.5[9]m.

EXAMPLE 123 2-(3-[5-phenylpent-1(E)enyl]phenyl]ethanol ##STR121##

2.8 g (8.3 mmol) 1-(3-bromophenyl)-5-phenylpentene was dissolved in 30ml dry tetrahydrofuran and cooled to -78° C. under argon. 5 ml (8.3mmol) t-butyllithium solution in pentane was added. After 15 minutes 2ml ethyleneoxide was added and the solution was allowed to reach roomtemperature. It was poured into ammonium chloride solution and extractedtwice with ether. The combined extracts were washed with saturatedsodium chloride solution then concentrated in vacuo. The residue waschromatographed on 80 g of silica gel (Merck Si60, 0.063-0.200 mm) togive a fraction which on concentration in vacuo gave a colourless liquid1.4 g.

Yield: 53% of theory

TLC R_(f) : 0.18 (ether-hexane 1:1)

NMR (CDCl₃, 60 MHz): 1.4-1.8[6] m, 2.1[1] s, 2.60[2] t, J=7 Hz, 2.80[2]t, J=7 Hz, 3.80[2] t, J=7 Hz, 5.6-6.0[1] m, 6.3[1] d, J=4 Hz, 6.7-7.3[9]m.

EXAMPLE 124 2-(3-[4-phenoxybut-1(E)enyl]phenyl)ethanol ##STR122##

Following the procedure of example 123 but using 1.22 g (4 mmol)1-(3-bromophenyl)-4-phenoxybutene gave an oily product afterchromatography 0.44 g.

Yield: 40% of theory

TLC R_(f) : 0.12 (ether-hexane 1:1)

NMR (CDCl₃, 60 MHz): 1.6-1.8[2] m, 2.75[2] t, J=7 Hz, 3.75[2] t, J=7 Hz,3.99[2] dt, J=7 Hz, 1.5 Hz, 5.6-6.0[1] m, 6.3[1] d, J=4 Hz, 6.7-7.3[9]m.

EXAMPLE 125 2-(3-[5-phenylpentyl]phenyl)ethanol ##STR123##

1.4 g (2-3-[5-phenylpentenyl]phenyl)ethanol in 100 ml ethyl acetate wastreated with 200 mg 10% palladium on charcoal and hydrogen at 1 bar for1 hour. The mixture was filtered through celite and concentrated invacuo to give a colorless oil 1.42 g.

Yield: 99% of theory

TLC R_(f) : 0.18 (ether-hexane 1:1)

NMR (CDCl₃, 60 MHz): 1.4-1.8[6] m, 2.1[1] s, 2.6[4] t, J=7 Hz, 2.80 [2]t, J=7 Hz, 3.8[2] t, J=7 Hz, 7.1[4] s, 7.2[5] s.

EXAMPLE 126 2-(3-[4-phenoxybutyl]phenyl)ethanol ##STR124##

0.44 g 2-(3-[4-phenoxybutenyl]phenylethanol was hydrogenated followingthe procedure of Example 125 to give a colorless oil 0.44 g.

Yield: 99% of theory

TLC R_(f) : 0.12 (ether-hexane 1:1)

NMR (CDCl₃, 60 MHz): 1.6-1.9[4] m, 2.1[1] s, 2.5-2.8[2] m, 2.73[2] t,J=7 Hz, 3.72[2] t, J=7 Hz, 3.8-4.0[2] m, 6.8-7.4[9] m.

EXAMPLE 127 1-(3-[2-bromoethyl]phenyl)-5-phenylpentane ##STR125##

Following the procedure of Example 118 1.4 g (5.3 mmol) of2.(3-[5-phenylpentyl]phenyl)ethanol gave an oily product 1.62 g.

Yield: 96% of theory

TLC R_(f) : 0.62 (ether-hexane 1:1)

NMR (CDCl₃, 60 MHz): 1.4-1.7[6] m, 2.53[4] t, J=7 Hz, 3.2-3.3[4] m,6.85-6.96[4] m, 7.06[5] s.

EXAMPLE 128 1-(3-[2-bromoethyl]phenyl)-4-phenoxybutane ##STR126##

Following the procedure for Example 118 0.44 g (1.6 mmol)2-(3-[4-phenoxybutyl]phenyl)ethanol gave an oily product 0.38 g.

Yield 70% of theory

TLC RF 0.55 (ether-hexane 1:1)

NMR (CDCl₃, 60 MHz): 1.6-1.8[4] m, 2.5-2.8[2] m, 2.9-3.6 [4] m,3.8-4.0[2] m, 6.7-7.4[9] m.

EXAMPLE 129 2-(3-[5-phenylpentyl]phenyl)ethyltriphenylphosphoniumbromide ##STR127##

0.99 g (3 mmol) 1-(3-[2-bromoethyl]phenyl)-5-phenylpentane was heatedwith 0.78 g (3 mmol) triphenylphosphine at 90° C. for 2 days in theabsence of solvent. The glassy solid was dissolved in dichloromethaneand chromatographed on 50 g silica gel eluting initially withdichloromethane than with 10% methanol in dichloromethane. Removal ofsolvent in vacuo gave a glassy solid 1.62 g.

Yield: 91% of theory

TLC R_(f) : 0.20 (dichloromethane:methanol 10:1)

NMR (CDCl₃, 60 MHz): 1.2-1.7[6] m, 2.2-2.6[4] m, 2.7-3.1[2] m,3.7-4.0[2] m, 6.4-6.7[4] m, 6.5-6.8[5] m, 7.2-7.6[15] m.

EXAMPLE 130 2-(3-[4-phenoxybutyl]-phenyl)ethyl triphenylphosphoniumbromide ##STR128##

0.37 g (1.1 mmol) 1-(3-[2-bromoethyl]phenyl)-4-phenoxybutane and 0.29 g(1.1 mmol) triphenylphosphine were refluxed for 6 days in 10 ml ethanol.The solution was concentrated in and chromatographed on 40 g silica gelwith dichloromethane and then 10% methanol-dichloromethane. Thefractions were concentrated in vacuo to give a colorless glass 0.50 g.

Yield: 76% of theory

TLC R_(f) : 0.22 (dichloromethane:methanol 9:1)

NMR (CDCl₃, 60 MHz): 1.7-1.9[4] m, 2.5-2.9[4] m, 2.7-3.1[2] m,3.7-4.0[4] m, 6.8-7.4[9] m, 7.5-8.0[15] m.

EXAMPLE 131 Ethyl6-(4-carbethoxybenzyl)-9-(3-[5-phenylpentyl]-phenyl)-non-7(Z)enoate##STR129##

Following the procedure of Example 121 0.81 g (1.4 mmol)2-(3-[5-phenylpentyl]phenyl)ethyltriphenylphosphonium bromide and 0.42 g(1.4 mmol) ethyl 7-(4-carbethoxyphenyl)-6-formylheptenoate gave an oilyproduct which was chromatographed on 40 g silica gel (Woelm 0.040-0.063mm) with ether:hexane (3.17) to give a fraction which on concentrationin vacuo gave a colourless oil 213 mg.

Yield: 28% of theory

TLC R_(f) : 0.28 (ether:hexane 1:4)

NMR (CDCl₃, 60 MHz): 1.33[6] t, J=7 Hz, 1.5-1.8[13] m, 2,17[2] t, J=7Hz, 2.3-2.7[6] m, 2.96[2] d, J=6 Hz, 3.95[2] q, J=7 Hz, 4.23[2] q, J=7Hz, 5.05[1] d, J=10 Hz, 5.35[1] dt, J=10 Hz, J=6 Hz, 6.6[2] m, 6.8[2] m,6.95-7.05[7] m, 7.74[2] d, J=7 Hz.

EXAMPLE 1326-(4-carboxybenzyl)-9-(3-[5-phenylpentyl]phenyl)-7(Z)nonenoic acid##STR130##

The product of example 131 was saponified by dissolving in 2 ml THF andrefluxing for 24 hours with 2 ml 1M dosium hydroxide solution. Thesolution was acidified with 1M hydrochlorid acid and extracted twicewith ethyl acetate. The combined organic phases were washed withsaturated sodium chloride solution, dried with magnesium sulphate thenconcentrated in vacuo to give a waxy whit solid 180 mg.

Recrystallization from ether-hexane gave a powder m.p. 123°-124° C.

Yield: 94% of theory

HPLC Lichrosorb RP-18 (7 μM) column MeCN:H₂ O AcOH 90:10; 0.1 pH 5.6 at1 ml/minute t_(R) 5.7 min.

NRM (CDCl₃, 60 MHz): 1.4-1.8[13] m, 2.1-2.7[9] m, 3.05[2] d, J=6 Hz,5.0-5.6[2] m, 6.7[2] s, 6.9[2] s, 7.0-7.3[7] m, 7.92[2] d, J=8 Hz.

EXAMPLE 133 Ethyl6-(4-carbethoxybenzyl)-9-(3-[4-phenoxybutyl]-phenyl)non-7(Z)enoate##STR131##

Following the procedure of Example 121 0.43 g (0.7 mmol)2-(3-[4-phenoxybutoxy]phenyl)ethyl triphenylphosphonium bromide and 0.23g (0.7 mmol) ethyl 7-(4-carbethoxyphenyl)-6-formyl heptanoate gave anoily product which was chromatographed on 25 g silica gel (Woelm0.040-0.063 mm) with ether-hexane 1:4 to give a fraction which onconcentration in vacuo gave an oil 154 mg.

Yield: 38% of theory

TLC R_(f) : 0.28 (ether:hexane 1:4)

NMR (CDCl₃, 60 MHz): 1.20[3] t, J=7 Hz, 1.35[3] t, J=7 Hz, 1.3-1.6[4] m,1.6-1.9[6] m, 2.20[2] t, J=7 Hz, 2.5-2.7[5] m, 3.0[2] d, J=6 Hz, 3.85[2]m, 4.05[2] q, J=7 Hz, 4.25[2] q, J=7 Hz, 5.05[1] m, 5.35[1] dt, J=9 Hz,J=4 Hz, 6.82[2] d, J=8 Hz, 6.6-7.0[5] m, 7.06 d, J=8 Hz, 7.0-7.3[2] m,7.87[2] d, J=8 Hz.

EXAMPLE 1346-(4-carboxybenzyl)-9-(3-[4-phenoxybutyl]phenyl)non-7(Z)enoic acid##STR132##

The product of example 133 was saponified by dissolving in 3 mltetrahydrofuran and refluxing for 18 hours with 3 ml aqueous lithiumhydroxide solution (10 mg/ml). The solution was then acidified with 1Mhydrochlorid acid and extracted twice with ethyl acetate. The combinedorganic phases were washed with saturated sodium chloride solution,dried with magnesium sulphate then concentrated in vacuo giving a whitesolid 80 mg m.p. 93°-95° C.

Yield: 58% of theory

HPLC Lichrosorb RP-18 (7 μM) column. MeCN:H₂ O: AcOH 70:30:0.1, pH 5.6at 1 ml/minute t_(R) 12.7 minutes

NMR (CDCl₃, 60 MHz): 1.25-1.9[12] m, 2.25[2] t, J=7 Hz, 2.3-2.7[5] m,3.05[2] d, J=6 Hz, 3.85[2] t, J=6 Hz, 5.05[1] m, 5.35[1] dt, J=9 Hz, J=4Hz, 6.65[3] s, 6.80[2] d, J=8 Hz, 6.75-7.0[2] m, 7.07[4] d, J=8 Hz,7.85[2] d, J=8 Hz.

EXAMPLE 135 Methyl 4-hydroxybutanoate ##STR133##

8.61 g (0.1 mol) γ-butyrolactone in 100 ml dry methanol was stirred for1 hour with 1.0 g (0.02 mol) sodium methoxide, under argon. 1.1 g (0.02mol) ammonium chloride was added and the solvent removed in vacuo. Theresulting liquid was dissolved in dichloromethane and washed withsaturated sodium chloride solution. The organic phase was dried withmagnesium sulphate and concentrated in vacuo to give a colorless oil10.3 g.

Yield: 87% of theory

NMR (CDCl₃, 60 MHz): 1.85[2] t, J=7 Hz, 2.40[2] t, J=7 Hz, 3.57[2] t,J=7 Hz, 3.67[3] s, 4.1[1] s.

EXAMPLE 136 Methyl-4-oxobutanoate ##STR134##

To 10.3 g (86 mmol) methyl 4-hydroxybutanoate in 100 ml drydichloromethane was added 20 g (93 mmol) pyridinium chlorochromate.After 4 hours this was filtered through a pad of florisil andconcentrated in vacuo. Kugelrohr distillation gave 3.95 g colourlessliquid. Boiling point: 50° C. 0.5 mbar

Yield: 39% of theory

NMR (CDCl₃, 60 MHz): 2.4[2] m, 2.6[2] m, 3.65[3] s, 9.72[1] s.

EXAMPLE 137 Methyl 4-trimethylsilyloxy-but-3enoate ##STR135##

Following the procedure of example 57 1.9 g (17 mmol) methyl4-oxobutenoate gave an oily residue which was purified by Kugelrohrdistillation as a colorless liquid 1.8 g.

Boiling point: 40° C. 0.5 mbar

Yield: 56% of theory

NMR (CDCl₃, 60 MHz): 0.18[9] s, 2.8-3.2[2] m, 3.63[3] s, 4.64[1] m,6.35[1] m.

EXAMPLE 138 Methyl 3-(4-carbomethoxyphenylthio)-4-oxobutanoate##STR136##

A solution of 2.0 g (10 mmol) 4-methoxycarbonylphenylsulphenic acidchloride in 25 ml carbon tetrachloride was slowly added to a solution of0.94 g (5 mmol) methyl 4-trimethylsilyloxybutene in 20 mldichloromethane at -20° C. After 1 hour 2 ml methanol was added and thesolvent removed at reduced pressure to give a semi-solid. This wastriturated with ether filtered and concentrated in vacuo to give an oilyresidue which was chromatographed on 50 g silica gel withethylacetate-hexane 1:4 to give a pale yellow oil 0.30 g.

Yield: 21% of theory

NMR (CDCl₃, 60 MHz): 2.83[2] m, 3.71[3] s, 3.75[1] m, 3.90[3] s, 7.48[2]d, J=9 Hz, 7.94[2] d, J=9 Hz, 9.62[1] d, J=1.5 Hz.

EXAMPLE 139 3-(4-Fluorophenoxy)propyl bromide ##STR137##

A mixture of 11.2 g (0.1 mol) of 4-fluorophenol, 16.5 g (0.12 mol) ofpulverized potassium carbonate, 20.2 g (0.1 mol) of 1,3-dibromopropaneand 100 ml of anhydrous dimethoxyethane was refluxed under nitrogen for6 hours and then cooled. The mixture was diluted with methylene chlorideand washed with water. The resultant organic product solution was driedover Na₂ SO₄ and evaporated in vacuo. The residue was chromatographed onsilica gel using cyclohexane elution to give pure product.

Yield: 29% of theory

NMR (CDCl₃, 60 MHz): 2.29[2] q, J=8 Hz, 3.59[2] t, J=8 Hz, 4.06[2] t,J=8 Hz, 6.8-7.0[4] m.

EXAMPLE 140 2-{3-[3-(4-Fluorophenoxy)propoxy]phenyl}ethanol ##STR138##

By following the procedure of example 9 and using3-(4-fluorophenoxy)propyl bromide rather than 4-phenoxybutyl bromide and2-(3-hydroxyphenyl)ethanol rather than 2-(4-hydroxyphenyl)ethanol, thetitle compound was prepared.

Yield: 95% of theory

NMR (CDCl₃, 250 MHz): 1.44[1] d, J=8 Hz, OH, 2.24[2] q, J=8 Hz, 2.83[2]t, J=8 Hz, 3.85[2] q, J=8 Hz, 4.11[2] t, J=8 Hz, 4.15[2] t, J=8 Hz,6.75-7.25[8] m.

EXAMPLE 141 2-{3-[3-(4-Fluorophenoxy)propoxy]phenyl}-ethyl bromide##STR139##

By following the procedure of example 8 and using the product of Example140 as starting material the title bromide was prepared.

Yield: 74% of theory

NMR (CDCl₃, 300 MHz): 2.25[2] q, J=8 Hz, 3.13[2] t, J=8 Hz, 3.55[2] t,J=8 Hz, 4.12[2] t, J=8 Hz, 4.16[2] t, J=8 Hz, 6.75-7.26[8] m.

EXAMPLE 142 2-{3-[3-(4-Fluorophenoxy)propoxy]phenyl}-ethyltriphenylphosphonium bromide ##STR140##

A solution of 20 mmol of bromide (example 141) and 30 mmol of triphenylphosphine in 60 ml of ethanol was refluxed 20 hours under nitrogen andthen cooled and evaporated in vacuo. The residue was chromatographed onsilica gel using first CHCl₃ to elute starting material residues andthen 5% CH₃ OH in CHCl₃ to elute the product. Evaporation of purefractions yielded the title compound as a viscous oil.

Yield: 50% of theory

NMR (CDCl₃, 300 MHz): 2.15-2.27[2] m, 2.95-3.1[2] m, 4.04-4.24[6] m,6.7-7.15[8] m, 7.65-7.0[15] m.

EXAMPLE 1436-(4-Methoxycarbonylbenzyl)-9-{3-[3-(4-fluorophenoxy)propoxy]benzyl}-7(Z)-nonenoicacid methyl ester ##STR141##

1.24 g (2 mmol) of the product of example 142 was dissolved in 25 ml ofanhydrous tetrahydrofuran under argon and then 140 mg (4 mmol) of sodiumhydride (80% in mineral oil) was added. The resultant mixture wasrefluxed under argon for 30 minutes and then cooled to 0° C. Then asolution of 450 mg (1.5 mmol) of6-formyl-7-(4-methoxycarbonylphenyl)heptanoic acid methyl ester in 1.5ml anhydrous tetrahydrofuran was added quickly dropwise. The resultantmixture was stirred 15 min. at 0° C. and then 15 minutes at roomtemperature and then 1 hour at reflux. The product was isolated as inexample 67 to give 0.35 g of pure product.

Yield: 41% of theory

NMR (CDCl₃, 300 MHz): 1.2-1.7[6] m, 2.2-2.3[4] m, 2.5-2.6[1] m,2.65-2.8[2] m, 3.0[1] dd, J=14.8 Hz, 3.13[1] dd, J=14.8 Hz, 3.65[3] s,3.9[3] s, 4.07-4.17[4] m, 5.21[1] t, J=10 Hz, 5.51[1] dt, J=10.7 Hz,6.45-7.23[10] m, 7.93[2] d, J=8 Hz.

EXAMPLE 1446-(4-Carboxybenzyl)-9-{3-[3-(4-fluorophenoxy)-propoxy]benzyl}-7-(Z)-nonenoicacid ##STR142##

Using the ester product of Example 143 and the procedure of example 68the title compound was prepared.

Yield: 85% of theory

NMR (CDCl₃, 300 MHz): 1.2-1.7[6] m, 2.23[2] q, J=8 Hz, 2.33[2] t, J=8Hz, 2.5-2.8[3] m, 3.03[1] dd, J=14.8 Hz, 3.14[1] dd, J=14.8 Hz,4.04-4.15[4] m, 5.22[1] t, J=10 Hz, 5.54[1] dt, J=10.7 Hz, 6.5-7.3[10]m, 7.97[2] d, J=8 Hz.

EXAMPLE 145 Animals-Male Dunkin Hartley 350-400 g (Interfauna)

1. Preparation

A guinea-pig was killed by a blow to the head and the trachea placed inTyrodes solution plus indomethacin (3×10⁻⁶ M). The trachea was cut openlongitudinally opposite the trachealis muscle and alternating transversecuts made across three quarters of the tissue width. The preparation wasopened out as a zig-zag-chain and suspended in a 10 ml tissue-bathcontaining Tyrodes solution with indomethacin (3×10⁻⁶ M) at 37° C.gassed with 5% CO₂ in oxygen. Tissue movement was monitored with a HugoSachs isotonic transducer with a load of 250-500 mg.

2. Experimental Procedure

Upon equilibration maximal response was determined using 10⁻⁴ and 3×10⁻⁴M histamine. The histamine was washed out and Tyrodes exchanged forTyrodes plus indomethacin, L-serine borate (45 mM) and L-cysteine (10mM). When the tissues had re-equilibrated one of each set of fourpreparations was treated with a series of 10 μl volumes of the vehiclecontrol EtOH. The other three were each treated with cumulativeadditions of the test drug to give a tissue-bath concentration from10⁻¹¹ -10⁻⁵ M. Fifteen minutes after the final addition of test drug orEtOH a cumulative concentration response curve for LTD₄ (10⁻¹⁰ -10⁻⁶ M)was applied. When maximal LTD₄ -concentration was reached the tissueswere discarded.

3. Materials

Indomethacin, LTD₄ (Leukotrien D₄), boric acid, L-cysteine and L-serine.

Tyrodes solution consisted of the following ANALAR grade substances (mM)dissolved in distilled water: NaCl 137, MgCl₂ 2.1, KCl 2.7, NaH₂ DO₄0.5, CaCl₂ 2.4, NaHCO₃ 11.9, D-glucose 9.2.

RESULTS

Contractions were normalised to the histamine-induced maximum for eachpreparation. The responses to analogue, LTD₄ and LTD₄ plus analogue werethen expressed as a percentage of the maximum LTD₄ response in theappropriate control preparation. EC₅₀ (that concentration required toinduce a 50% maximal LTD₄ response) values for `test` and controltissues were calculated using a least squares linear regression program.These values were used to calculate a pK_(B) to quantify the degree ofantagonism where appropriate.

It will be appreciated that the instant specification and claims are setforth by way of illustration and not limitation, and that variousmodifications and changes may be made without departing from the spiritand scope of the present invention.

What is claimed is:
 1. A phosphorous compound of the formula ##STR143##wherein R² and R³ are identical or different and represent hydrogen,alkyl, alkoxy, halogen, trifluoromethyl, trifluoromethoxy, cyano ornitro,U represents a group of the formula ##STR144## where R⁶ and R⁷ areidentical or different and denote alkyl or phenyl andV denotes tosylateanion, T and Z are identical or different and represent oxygen or adirect bond, m represents a number 0 to 7 and n represents a number 1 to10.